2-(iminomethyl) amino-phenyl derivatives, preparation, application as medicines and pharmaceutical compositions containing same

ABSTRACT

A compound of the formula                    
     wherein the substituents are defined as in the specification and their pharmaceutically acceptable salts having NOS and ROS activity.

A subject of the present invention is new derivatives of2-(iminomethyl)amino-phenyl which have an inhibitory activity onNO-synthase enzymes producing nitrogen monoxide NO and/or an activitywhich traps the reactive oxygen species (ROS). The invention relates tothe derivatives corresponding to general formula (I) defined below,their preparation methods, the pharmaceutical preparations containingthem and their use for therapeutic purposes, in particular their use asNO-synthase inhibitors and selective or non selective traps for reactiveoxygen species.

Given the potential role of NO and the ROS's in physiopathology, the newderivatives described corresponding to general formula (I) may producebeneficial or favourable effects in the treatment of pathologies wherethese chemical species are involved. In particular:

cardiovascular and cerebro-vascular disorders including for exampleatherosclerosis, migraine, arterial hypertension, septic shock, ischemicor hemorragic cardiac or cerebral infarctions, ischemias and thromboses.

disorders of the central or peripheral nervous system such as forexample neurodegenerative diseases where there can in particular bementioned cerebral infarctions, sub-arachnoid haemorrhaging, ageing,senile dementias including Alzheimer's disease, Huntington's chorea,Parkinson's disease, Creutzfeld Jacob disease and prion diseases,amyotrophic lateral sclerosis but also pain, cerebral and bone marrowtraumas, addiction to opiates, alcohol and addictive substances,erective and reproductive disorders, cognitive disorders,encephalopathies, encephalopathies of viral or toxic origin.

disorders of the skeletal muscle and neuromuscular joints (myopathy,myosis) as well as cutaneous diseases.

proliferative and inflammatory diseases such as for exampleatherosclerosis, pulmonary hypertension, respiratory distress,glomerulonephritis, portal hypertension, psoriasis, arthrosis andrheumatoid arthritis, fibroses, amyloidoses, inflammations of thegastro-intestinal system (colitis, Crohn's disease) or of the pulmonarysystem and airways (asthma, sinusitis, rhinitis).

organ transplants.

auto-immune and viral diseases such as for example lupus, AIDS,parasitic and viral infections, diabetes, multiple sclerosis.

cancer.

neurological diseases associated with intoxications (Cadmium poisoning,inhalation of n-hexane, pesticides, herbicides), associated withtreatments (radiotherapy) or disorders of genetic origin (Wilson'sdisease).

all the pathologies characterized by an excessive production ordysfunction of NO and/or ROS's.

In all these pathologies, there is experimental evidence demonstratingthe involvement of NO or ROS's (J. Med. Chem. (1995) 38, 4343-4362; FreeRadic. Biol. Med. (1996) 20, 675-705; The Neuroscientist (1997) 3,327-333).

Furthermore, NO Synthase inhibitors, their use and more recently thecombination of these inhibitors with products having antioxidant orantiradicular properties have already been described in previous Patents(respectively U.S. Pat. No. 5,081,148; U.S. Pat. No. 5,360,925 and anunpublished Patent Application).

A subject of the present invention is the derivatives of2-(iminomethyl)amino-phenyl, their preparation and their therapeuticuse.

The compounds of the invention correspond to general formula (I):

in which:

A represents:

 either a

 radical in which R₁ and R₂ represent, independently, a hydrogen atom, ahalogen, the OH group, a linear or branched alkyl or alkoxy radicalhaving from 1 to 6 carbon atoms,

R₃ represents a hydrogen atom, a linear or branched alkyl radical havingfrom 1 to 6 carbon atoms or a —COR₄ radical,

R₄ represents a linear or branched alkyl radical having from 1 to 6carbon atoms,

 or a

 radical in which R₃ has the meaning indicated above

 or a

 radical in which R₅ represents a hydrogen atom, the OH group or alinear or branched alkyl or alkoxy radical having from 1 to 6 carbonatoms;

B represents a linear or branched alkyl radical having from 1 to 6carbon atoms, carbocyclic or heterocyclic aryl with 5 or 6 memberscontaining from 1 to 4 heteroatoms chosen from O, S, N and in particularthe thiophene, furan, pyrrole or thiazole radicals, the aryl radicalbeing optionally substituted by one or more groups chosen from thelinear or branched alkyl, alkenyl or alkoxy radicals having from 1 to 6carbon atoms;

X represents —Z₁—, —Z₁—CO—, —CH═CH—CO—, —Z₁—NR₃—CO—, —Z₁—NR₃—CS—,—Z₁—NR₃—SO₂— or a single bond;

Y represents a radical chosen from the —Z₂—Q, piperazine,homopiperazine, 2-methylpiperazine, 2,5-dimethyl-piperazine,4-aminopiperidine, —NR₃—Z₂—Q—, —NR₃—CO—Z₂—Q—, —NR₃—NH—CO—Z₂—,—NH—NH—Z₂—, —NR₃—O—Z₂—, —NR₃—SO₂—NR₃—Z₂—, —O—Z₂—Q—, —O—CO—Z₂—Q— or—S—Z₂—Q— radicals, in which Q represents a single bond, O—Z₃, R₃—N—Z₃ orS—Z₃;

Z₁, Z₂ and Z₃ represent independently a single bond or a linear orbranched alkylene radical having from 1 to 6 carbon atoms; preferably,Z₁, Z₂ and Z₃ represent —(CH₂)_(m)—, m being an integer comprisedbetween 0 and 6;

R₆ represents a hydrogen atom or an OH group;

or are salts of the latter.

The compounds of general formula (I) containing an asymmetrical centreare of isomeric form. The racemic and enantiomeric forms of thesecompounds also form part of this invention.

The compounds of the invention can exist in the state of bases or ofaddition salts in particular with organic or inorganic acids or withbases, and in particular in the state of hydrates, hydrochlorides,dihydrochlorides, fumarates or hemifumarates.

By linear or branched alkyl having from 1 to 6 carbon atoms is meant inparticular the methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl and tert-butyl, pentyl, neopentyl, isopentyl, hexyl, isohexylradicals. By linear or branched alkoxy having from 1 to 6 carbon atomsis meant radicals the alkyl radical of which has the meaning indicatedpreviously.

By halogen is meant fluorine, chlorine, bromine or iodine atoms.

A particular subject of the invention is the following compounds ofgeneral formula (I), described in the examples (in the form of salts incertain cases):

3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-{4-[(2-thienyl(imino)methyl)amino]phenyl}-benzamide;

3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-{4-[[(2-thienyl(imino)methyl)amino]phenyl]methyl}-benzamide;

4-acetoxy-3,5-dimethoxy-N-{4-[[(2-thienyl(imino)methyl)amino]phenyl]methyl}-benzamide;

3,5-dimethoxy-4-hydroxy-N-{4-[[(2-thienyl(imino)methyl)amino]phenyl]methyl}-benzamide;

3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-{4-[2-[(2-thienyl(imino)methyl)amino]phenyl]ethyl}-benzamide;

4-acetoxy-3,5-dimethoxy-N-{4-[2-[(2-thienyl-(imino)methyl)-amino]phenyl]ethyl}-benzamide;

3,5-dimethoxy-4-hydroxy-N-{4-[2-[(2-thienyl-(imino)methyl)-amino]phenyl]ethyl}-benzamide;

3,4,5-trihydroxy-N-{4-[2-[(2-thienyl(imino)methyl)-amino]phenyl]ethyl}-benzamide;

N-{4-[4-[3,5-bis-(1,1-dimethylethyl)-4-hydroxybenzoyl]-1-piperazinyl]-phenyl}-2-thiophenecarboximidamide;

N-{4-[4-[3,5-bis-(1,1-dimethylethyl)-4-hydroxybenzyl]-1-piperazinyl]phenyl}-2-thiophenecarboximdamide;

N-{4-[4-[3,5-dimethoxy-4-hydroxybenzoyl]-1-piperazinyl]-phenyl}-2-thiophenecarboximidamide;

3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-N-{4-[(2-thienyl(imino)methyl)amino]phenyl}-2H-1-benzopyran-2-carboxamide;

N-{4-[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)carbonyl]-1-piperazinyl]phenyl}-2-thiophenecarboximidamide;

N-{4-[4-[(5-methoxy-1H-indol-3-yl)methylcarbonyl]-1-piperazinyl]phenyl}-2-thiophenecarboximidamide;

N-[4-[4-[{3-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-1-oxo-2-propenyl}-1-piperazinyl]-phenyl]]-2-thiophenecarboximidamide;

3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-{3-[[(2-thienyl(imino)methyl)amino]phenyl]methyl}-benzamide;

N-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N′-{{4-[(2-thienyl(imino)methyl)amino]phenyl}methyl}-urea;

N-[5-[{3-(3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl)-1-oxo-2-propenyl}amino]-2-hydroxyphenyl]-2-thiophenecarboximidamide;

N-[3-[{3-(3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl)-1-oxo-2-propenyl}-amino]-4-hydroxyphenyl]-2-thiophenecarboximidamide;

N-{4-[4-[3,4,5-trihydroxybenzoyl]-1-piperazinyl]phenyl}-2-thiophenecarboximidamide;

N-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N′-{{4-[(2-thienyl(imino)methyl)amino]phenyl}carbonylamino}-urea;

N-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N′-{{4-[(2-thienyl(imino)methyl)amino]phenyl}methyl}-thiourea;

N-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N′-{2-{4-[(2-thienyl(imino)methyl)amino]phenyl}ethyl}-urea;

N-(4-{4-[(3,4-dihydro-6-methoxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)carbonyl]-1-piperazinyl}phenyl)-2-thiophenecarboximidamide;

N-[4-{4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)carbonyl]-1H-1,4-diazepin-1-yl}phenyl]-2-thiophenecarboximidamide;

(R)-N-{4-[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)carbonyl]-1-piperazinyl]phenyl}-2-thiophenecarboximidamide;

(S)-N-{4-[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)carbonyl]-1-piperazinyl]phenyl}-2-thiophenecarboximidamide;

3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-{2-[3-[(2-thienyl(imino)methyl)amino]phenyl]ethyl}-benzamide;

N-{4-(4-[2-(3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl)-1-oxo-ethyl]-1-piperazinyl)phenyl}-2-thiophene-carboximidamide;

2-{4-[(2-thienyl(imino)methyl)amino]phenyl}ethyl3,5-bis-(1,1-dimethylethyl)-4-hydroxy-benzoate

2-{3-[(2-thienyl(imino)methyl)amino]phenyl}ethyl3,5-bis-(1,1-dimethylethyl)-4-hydroxy-benzoate

2-{2-[(2-thienyl(imino)methyl)amino]phenyl}ethyl3,5-bis-(1,1-dimethylethyl)-4-hydroxy-benzoate

as well as their salts, in particular their hydrochlorides,dihydrochlorides, fumarates or hemi-fumarates.

There will generally be preferred the compounds of general formula (I)for which:

X represents a linear or branched alkylene radical having from 1 to 6carbon atoms and Y represents a piperazine, homopiperazine,2-methylpiperazine, 2,5-dimethylpiperazine, 4-aminopiperidine,—NR₃—Z₂—Q—, —NR₃—NH—CO—Z₂—, —NH—NH—Z₂— or —NR₃—O—Z₂— radical;

 or

X represents —Z₁—CO— or —CH═CH—CO— and Y represents a piperazine,homopiperazine, 2-methylpiperazine, 2,5-dimethylpiperazine,4-aminopiperidine, —NR₃—Z₂—Q—, —NR₃—NH—CO—Z₂—, —NH—NH—Z₂—, —NR₃—O—Z₂—,—O—Z₂—Q— radical or —NR₃—CO—Q′— radical with Q′=R₃—N—Z₃;

 or

X represents —Z₁—NR₃—CO— and Y represents —Z₂—Q—, —NH—Z₂—Q—,—NH—CO—Z₂—Q″— with Q″=O—Z₃—, R₃—N—Z₃— or S—Z₃—, or Y represents—NR₃—SO₂—NR₃—Z₂— or —O—Z₂—Q—;

 or

X represents —Z₁—NH—CO— and Y represents a piperazine, homopiperazine,2-methylpiperazine, 2,5-dimethylpiperazine, 4-aminopiperidine,—NR₃—Z₂—Q—, —NR₃—NH—CO—Z₂—, —NH—NH—Z₂— or —NR₃—O—Z₂— radical;

 or

X represents —Z₁—NR₃—SO₂— and Y represents —Z₂—Q″— with Q″=O—Z₃—,R₃—N—Z₃— or S—Z₃—, or Y represents —NR₃—Z₂—Q—;

 or

X represents —Z₁— and Y represents —O—CO—Z₂—Q—;

 or

X represents —Z₁—NR₃—CS— and Y represents —NH—Z₂—Q—, or a piperazine,homopiperazine, 2-methylpiperazine, 2,5-dimethyl-piperazine,4-aminopiperidine, —NR₃—Z₂—Q—, —NH—NH—Z₂— or —NR₃—O—Z₂— radical;

 or

X represents a bond and Y represents —O—Z₂—NH—, —S—Z₂—NH—.

Moreover, the X-Y group will preferably be chosen from the followingradicals:

in which T represents a single bond, the —NR₃— radical or the —CO—NR₃—radical, or

in which R_(p) represents a hydrogen atom or a methyl radical, or

in which U represents a —Z₂, —NR₃—CO—, —CO—Z₂—O—, —CO—, —NR₃— radical oran oxygen atom, or

the Z₁, Z₂ and R₃ radicals having the meaning indicated above.

In a preferential manner, the compounds according to the invention willbe one of the following compounds:

3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-{4-[2-[(2-thienyl(imino)methyl)amino]phenyl]ethyl}-benzamide;

3,4,5-trihydroxy-N-{4-[2-[(2-thienyl(imino)methyl)-amino]phenyl]ethyl}-benzamide;

N-{4-[4-[3,5-bis-(1,1-dimethylethyl)-4-hydroxybenzoyl]-1-piperazinyl]phenyl}-2-thiophenecarboximidamide;

N-{4-[4-[3,5-bis-(1,1-dimethylethyl)-4-hydroxybenzyl]-1-piperazinyl]phenyl}-2-thiophenecarboximidamide;

3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-N-{4-[(2-thienyl(imino)methyl)amino]phenyl}-2H-1-benzopyran-2-carboxamide;

N-{4-[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)carbonyl]-1-piperazinyl]phenyl}-2-thiophenecarboximidamide;

N-{4-[4-[(5methoxy-1H-indol-3-yl)methylcarbonyl]-1-piperazinyl]phenyl}-2-thiophenecarboximidamide;

3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-{3-[[(2-thienyl(imino)methyl)amino]phenyl]methyl}-benzamide;

N-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N′-{{4-[(2-thienyl(imino)methyl)amino]phenyl}methyl}-urea;

N-[5-[{3-(3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl)-1-oxo-2-propenyl}-amino]-2-hydroxyphenyl]-2-thiophenecarboximidamide;

N-[3-[{3-(3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl)-1-oxo-2-propenyl}-amino]-4-hydroxyphenyl]-2-thiophenecarboximidamide;

N-{4-[4-[3,4,5-trihydroxybenzoyl]-1-piperazinyl]phenyl}-2-thiophenecarboximidamide;

N-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N′-{{4-[(2-thienyl(imino)methyl)amino]phenyl}carbonylamino}-urea;

or a salt of one of the latter, in particular a hydrochloride,dihydrochloride, fumarate or hemi-fumarate of one of the latter.

Other preferred compounds for the invention will be the followingcompounds:

4-acetoxy-3,5-dimethoxy-N-{4-[2-[(2-thienyl-(imino)methyl)-amino]phenyl]ethyl}-benzamide;

3,5-dimethoxy-4-hydroxy-N-{4-[2-[(2-thienyl-(imino)methyl)-amino]phenyl]ethyl}-benzamide;

or a salt of one of the latter, in particular a hydrochloride,dihydrochloride, fumarate or hemi-fumarate of one of the latter.

Quite particularly preferred compounds of the invention will be asfollows:

N-{4-[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)carbonyl]-1-piperazinyl]phenyl}-2-thiophenecarboximidamide;

(R)-N-{4-[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)carbonyl]-1-piperazinyl]phenyl}-2-thiophenecarboximidamide;

(S)-N-{4-[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)carbonyl]-1-piperazinyl]phenyl}-2-thiophenecarboximidamide;

or a salt of one of the latter, in particular a hydrochloride,dihydrochloride, fumarate or hemi-fumarate of one of the latter.

Finally, there will be particularly preferred for the invention thecompounds of general formula (I) presenting the followingcharacteristics:

either:

A represents:

X represents —CO— or —NH—CO—;

and Y represents an —NH—Z₂—Q— or piperazine radical, Q representing asingle bond or an O—Z₃, R₃—N—Z₃ or S—Z₃ radical, and Z₂ and Z₃representing independently a bond or a linear or branched alkyleneradical having from 1 to 6 carbon atoms and R₃ represents a hydrogenatom or a linear or branched alkyl radical having from 1 to 6 carbonatoms.

or: R₆ is an OH group.

A subject of the invention is also, as medicaments, the compounds ofgeneral formula (I) described previously or their pharmaceuticallyacceptable salts. It also relates to pharmaceutical compositionscontaining these compounds or their pharmaceutically acceptable salts,and the use of these compounds or of their pharmaceutically acceptablesalts for producing medicaments intended to inhibit neuronal NO synthaseor inductible NO synthase, to inhibit lipidic peroxidation or to providethe double function of NO synthase inhibition and lipidic peroxidation.

By pharmaceutically acceptable salt is meant in particular additionsalts of inorganic acids such as hydrochloride, sulphate, phosphate,diphosphate, hydrobromide and nitrate, or of organic acids, such asacetate, maleate, fumarate, tartrate, succinate, citrate, lactate,methane sulphonate, p-toluenesulphonate, pamoate, oxalate and stearate.The salts formed from bases such as sodium or potassium hydroxide alsofall within the scope of the present invention, when they can be used.For other examples of pharmaceutically acceptable salts, reference canbe made to “Pharmaceutical salts”, J. Pharm. Sci. 66:1 (1977).

The pharmaceutical composition can be in the form of a solid, forexample powders, granules, tablets, capsules, liposomes orsuppositories. Appropriate solid supports can be for example calciumphosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch,gelatin, methyl cellulose, sodium carboxymethyl cellulose,polyvinylpyrrolidine and wax.

The pharmaceutical compositions containing a compound of the inventioncan also be presented in the form of a liquid, for example, solutions,emulsions, suspensions or syrups. Appropriate liquid supports can be,for example, water, organic solvents such as glycerol or the glycols, aswell as their mixtures, in varying proportions, in water.

A medicament according to the invention can be administered by topical,oral or parenteral route, by intramuscular injection, etc.

The envisaged administration dose for the medicament according to theinvention is comprised between 0.1 mg and 10 g according to the type ofactive compound used.

The invention also offers, as new industrial products, the syntheticintermediates of the products of general formula (I), namely theproducts of general formula (II)A:

in which:

W represents an amino or nitro radical,

A represents:

 either a

 radical in which R₁ and R₂ represent, independently, a hydrogen atom, ahalogen, the OH group, a linear or branched alkyl or alkoxy radicalhaving from 1 to 6 carbon atoms,

R₃ represents a hydrogen atom, a linear or branched alkyl radical havingfrom 1 to 6 carbon atoms or a —COR₄ radical,

R₄ representing a linear or branched alkyl radical having from 1 to 6carbon atoms,

 or a

 radical in which R₃ has the meaning indicated above or a

 radical in which R₅ represents a hydrogen atom, the OH group or alinear or branched alkyl or alkoxy radical having from 1 to 6 carbonatoms;

X represents —Z₁—, —Z₁—CO—, —CH═CH—CO—, —Z₁—NR₃—CO—, —Z₁—NR₃—CS—,—Z₁—NR₃—SO₂— or a single bond;

Y represents a radical chosen from the —Z₂—Q, piperazine,homopiperazine, 2-methylpiperazine, 2,5-dimethylpiperazine,4-aminopiperidine, —NR₃—Z₂—Q—, —NR₃—CO—Z₂—Q—, —NR₃—NH—CO—Z₂—,—NH—NH—Z₂—, —NR₃—O—Z₂—, —NR₃—SO₂—NR₃—Z₂—, —O—Z₂—Q—, —O—CO—Z₂—Q— or—S—Z₂—Q— radicals, in which Q represents a single bond, O—Z₃, R₃—N—Z₃ orS—Z₃;

Z₁, Z₂ and Z₃ represent independently a single bond or a linear orbranched alkylene radical having from 1 to 6 carbon atoms; preferably,Z₁, Z₂ and Z₃ represent —(CH₂)_(m), m being an integer comprised between0 and 6;

R₆ represents a hydrogen atom or an OH group;

with the exception however of3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-(4-nitrophenyl)-benzamide;

or the salts of the latter.

Moreover, the invention offers in particular, as new industrialproducts, the following compounds, which are synthetic intermediates ofproducts of general formula (I):

3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-(4-aminophenyl)-benzamide;

3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-[(4-nitrophenyl)methyl]-benzamide;

3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-[(4-aminophenyl)methyl]-benzamide;

4-acetoxy-3,5-dimethoxy-N-[(4-nitrophenyl)methyl]-benzamide;

4-acetoxy-3,5-dimethoxy-N-[(4-aminophenyl)methyl]-benzamide;

3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-[2-(4-nitrophenyl)ethyl]-benzamide;

3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-[2-(4-aminophenyl)ethyl]-benzamide;

4-acetoxy-3,5-dimethoxy-N-[2-(4-nitrophenyl)ethyl]-benzamide;

4-acetoxy-3,5-dimethoxy-N-[2-(4-aminophenyl)ethyl]-benzamide;

3,4,5-trihydroxy-N-[2-(4-nitrophenyl)ethyl]-benzamide;

3,4,5-trihydroxy-N-[2-(4-aminophenyl)ethyl]-benzamide;

2,6-bis-(1,1-dimethylethyl)-4-{[4-(4-nitrophenyl)-1-piperazinyl]-carbonyl}-phenol;

2,6-bis-(1,1-dimethylethyl)-4-{[4-(4-aminophenyl)-1-piperazinyl]-carbonyl}-phenol;

2,6-bis-(1,1-dimethylethyl)-4-{[4-(4-nitrophenyl)-1-piperazinyl]-methyl}-phenol;

2,6-bis-(1,1-dimethylethyl)-4-{[4-(4-aminophenyl)-1-piperazinyl]-methyl}-phenol;

2,6-dimethoxy-4-{[4-(4-nitrophenyl)-1-piperazinyl]carbonyl}-phenol;

2,6-dimethoxy-4-{[4-(4-aminophenyl)-1-piperazinyl]carbonyl}-phenol;

3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-N-(4-nitrophenyl)-2H-1-benzopyran-2-carboxamide;

3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-N-(4-aminophenyl)-2H-1-benzopyran-2-carboxamide;

3,4-dihydro-2,5,7,8-tetramethyl-2-{4-[(4-nitrophenyl)-1-piperazinyl]-carbonyl}-2H-1-benzopyran-6-ol;

3,4-dihydro-2,5,7,8-tetramethyl-2-{4-[(4-aminophenyl)-1-piperazinyl]-carbonyl}-2H-1-benzopyran-6-ol;

1-[(5methoxy-1H-indol-3-yl)methylcarbonyl]-4-(4-nitrophenyl)-piperazine;

1-[(5methoxy-1H-indol-3-yl)methylcarbonyl]-4-(4-aminophenyl)-piperazine;

2,6-bis-(1,1-dimethylethyl)-4-{3-[4-(4-nitrophenyl)-1-piperazinyl]-3-oxo-2-propenyl}-phenol;

2,6-bis-(1,1-dimethylethyl)-4-{3-[4-(4-aminophenyl)-1-piperazinyl]-3-oxo-2-propenyl}-phenol;

3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-[(3-nitrophenyl)methyl]-benzamide;

3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-[(3-aminophenyl)methyl]-benzamide;

N-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N′-[(4-nitrophenyl)methyl]-urea;

N-[(4-aminophenyl)methyl]-N′-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-urea;

3-[(3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N-(4-hydroxy-3-nitrophenyl)-2-propenamide;

3-[(3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N-(4-hydroxy-3-aminophenyl)-2-propenamide;

3-[(3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N-(2-hydroxy-5-nitrophenyl)-2-propenamide;

3-[(3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N-(2-hydroxy-5-aminophenyl)-2-propenamide;

5-{[4-(4-nitrophenyl)-1-piperazinyl]carbonyl}-benzene-1,2,3-triol;

5-{[4-(4-aminophenyl)-1-piperazinyl]carbonyl}-benzene-1,2,3-triol;

N-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N′-[(4-nitrophenyl)-carbonylamino]-urea;

N-[(4-aminophenyl)carbonylamino]-N′-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-urea;

N-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N′-[(4-nitrophenyl)methyl]-thiourea;

N-[(4-aminophenyl)methyl]-N′-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-thiourea;

N-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N′-[2-(4-nitrophenyl)ethyl]-urea;

N-[2-(4-aminophenyl)ethyl]-N′-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-urea;

1-{[3,4-dihydro-6-methoxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl]carbonyl}-4-(4-nitrophenyl)piperazine;

1-{[3,4-dihydro-6-methoxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl]carbonyl}-4-(4-aminophenyl)piperazine;

hexahydro-4-(4-nitrophenyl)-1H-1,4-diazepine;

1-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)carbonyl]hexahydro-4-(4-nitrophenyl)-1H-1,4-diazepine;

1-(4-aminophenyl)-4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)carbonyl]hexahydro-1H-1,4-diazepine;

hydrochloride duN-[4-{4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)carbonyl]-1H-1,4-diazepin-1-yl}phenyl]-2-thiophenecarboximidamidehydrochloride;

(R)-3,4-dihydro-2,5,7,8-tetramethyl-2-{4-[(4-nitrophenyl)-1-piperazinyl]-carbonyl}-2H-1-benzopyran-6-ol;

(R)-3,4-dihydro-2,5,7,8-tetramethyl-2-{4-[(4-aminophenyl)-1-piperazinyl]-carbonyl}-2H-1-benzopyran-6-ol;

(S)-3,4-dihydro-2,5,7,8-tetramethyl-2-{4-[(4-nitrophenyl)-1-piperazinyl]-carbonyl}-2H-1-benzopyran-6-ol;

(S)-3,4-dihydro-2,5,7,8-tetramethyl-2-{4-[(4-aminophenyl)-1-piperazinyl]-carbonyl}-2H-1-benzopyran-6-ol;

3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-[2-(3-nitrophenyl)ethyl]-benzamide;

3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-[2-(3-aminophenyl)ethyl]-benzamide;

2-(4-nitrophenyl)ethyl 3,5-bis-(1,1-dimethylethyl)-4-hydroxybenzoate;

2-(4-aminophenyl)ethyl 3,5-bis-(1,1-dimethylethyl)-4-hydroxy-benzoate;

or their salts.

Finally, the invention offers processes for the preparation of compoundsof general formula (I) as defined above and consisting, for example, ofthe reaction in a lower alcohol such as methanol, ethanol, isopropylalcohol or t-butanol, preferably in isopropyl alcohol, at a temperaturecomprised between 20 and 90° C., for example at 50° C., and for 1 to 48hours, preferably for 15 to 24 hours, optionally in the presence of DMF,of a compound of general formula (III) as defined above with a compoundof general formula (IV)

said compound of general formula (IV) being optionally salified by amineral acid G, B having the meaning indicated above and L representinga leaving group and in particular an alkoxy, thioalkyl, sulphonic acid,halide, aryl alcohol or tosyl radical (other leaving groups well knownto a person skilled in the art which can optionally be used for theinvention are described in the following work: Advanced OrganicChemistry, J. March, 3rd Edition (1985), Mc Graw-Hill, p. 315).Preferably, G represents HCl, HBr or HI.

Other production processes can be envisaged and can be consulted in theliterature (for example: The Chemistry of amidines and imidates, Vol. 2,Saul PATAI and Zvi RAPPOPORT, John Wiley & Sons, 1991).

According to the invention, the compounds of general formula (I) can beprepared by the process described below.

Preparation of Compounds of General Formula (I):

The compounds of general formula (I) can be prepared from intermediatesof general formula (II) according to diagram 1.

The reduction of the nitro function of the intermediates of generalformula (II) is generally carried out by catalytic hydrogenation inethanol, in the presence of Pd/C, except when X=—CH═CH—CO— or Y=—O—CH₂—,the nitro group is selectively reduced using, for example, SnCl₂ (J.Heterocyclic Chem. (1987), 24, 927-930; Tetrahedron Letters (1984), 25,(8), 839-842). The reaction is then carried out by heating the mixtureto approx. 70° C., for at least three hours, in ethyl acetate, sometimeswith added ethanol.

The aniline derivatives of general formula (III) thus obtained can becondensed on derivatives of general formula (IV), for examplederivatives of O-alkyl thioimidate or S-alkyl thioimidate type, in orderto produce final compounds of general formula (I) (cf. diagram 1). Forexample, for B=thiophene, the derivatives of general formula (III) canbe condensed on S-methylthiophene thiocarboxamide hydriodide, preparedaccording to a method in the literature (Ann. Chim. (1962), 7, 303-337).Condensation can be carried out by heating in an alcohol (for example inmethanol or isopropanol), optionally in the presence of DMF at atemperature comprised between 50 and 100° C. for a duration generallycomprised between a few hours and overnight.

Preparation of Intermediates of General Formula (II):

The intermediates of general formula (II) can be prepared by differentprocesses depending on the chemical functions which are set up: amines,carboxamides, ureas, thioureas, sulphonamides, aminosulphonylureas,sulphamides, carbamates, ethers, esters, thioethers, acylureas, etc.:

When:

X=linear or branched alkylene radical having from 1 to 6 carbon atoms

and Y=piperazine, homopiperazine, 2-methylpiperazine,2,5-dimethylpiperazine, 4-aminopiperidine, —NR₃—Z₂—Q—, —NR₃—NH—CO—Z₂—,—NH—NH—Z₂—, —NR₃—O—Z₂—

The amines of general formula (II), diagram 2, in which A, X, Y and R₆are as defined above, can be obtained by nucleophile substitution of thehalogenated derivatives of general formula (VI) by an amine of generalformula (VII). The reaction is carried out, for example, in DMF in thepresence of K₂CO₃ at 20° C. The halogenated derivatives of generalformula (VI) can be accessed, for example, by bromation of the primaryalcohols of general formula (V) using PBr₃, at 0° C., in anhydrous THF.The alcohols of general formula (V) which are not commercially availablecan be prepared according to methods described in the literature(Tetrahedron Lett. (1983), 24, (24), 2495-2496).

The amines of general formula (VII) in which Y representshomopiperazine, 2,5-dimethylpiperazine, 4-aminopiperidine or moregenerally —NR₃—Z₂—NR₃— are synthesized in three stages from thecorresponding commercial diamines. The diamines are selectivelymono-protected in the form of the carbamate (Synthesis (1984), (12),1032-1033; Synth. Commun. (1990), 20, (16), 2559-2564) before reactionby nucleophile substitution on a fluoronitrobenzene, in particular4-fluoronitrobenzene. The amines, previously protected, are released atthe last stage, according to methods described in the literature (T. W.Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, SecondEdition (Wiley-Interscience, 1991)), in order to produce intermediatesof general formula (VII).

When:

X=—Z₁—CO—, —CH═CH—CO—

and Y=piperazine, homopiperazine, 2-methylpiperazine,2,5-dimethylpiperazine, 4-aminopiperidine, —NR₃—Z₂—Q—, —NR₃—NH—CO—Z₂—,—NH—NH—Z₂—, —NR₃—O—Z₂—

The carboxamides of general formula (II), diagram 3, in which A, X, Yand R₆ are as defined above, are prepared by condensation of thecommercial carboxylic acids of general formula (VIII) for X=—Z₁CO— andof general formula (IX) for X=—CH═CH—CO— with amines of general formula(VII). The non commercial acids can be synthesized according to methodssimilar to those described in the literature (J. Org. Chem. (1974), 39(2), 219-222; J. Amer. Chem. Soc. (1957), 79, 5019-5023, and CHIMIA(1991), 45 (4), 121-123 when A represents a6-alkoxy-2,5,7,8-tetramethylchromane radical). The amines of generalformula (VII) in which Y represents homopiperazine,2,5-dimethylpiperazine, 4-aminopiperidine, or more generally—NR₃—Z₂—NR₃— are prepared according to methods similar to thosedescribed in the previous paragraph. The carboxamide bonds are formedunder standard conditions for peptide synthesis (M. Bodanszky and A.Bodanszky, The Practice of Peptide Synthesis, 145 (Springer-Verlag,1984)) in THF, dichloromethane or DMF in the presence of a couplingreagent such as dicyclohexylcarbodiimide (DCC), 1.1′-carbonyldiimidazole(CDI) (J. Med. Chem. (1992), 35 (23), 4464-4472) or1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC orWSCI) (John Jones, The chemical synthesis of peptides, 54 (ClarendonPress, Oxford, 1991)).

When:

X=—Z₁—NR₃—CO—

and Y=—Z₂—Q—

The carboxamides of general formula (II) in which A, X, Y and R₆ are asdefined above can also be prepared, as in diagram 4, by peptidecondensation of an amine of general formula (X) with a commercial acidof general formula (XI). When X=—NR₃—CO— and R₃=H, the compounds ofgeneral formula (X) are anilines which are obtained by hydrogenation, inthe presence of a catalytic quantity of Pd/C, the correspondingnitrobenzene derivatives, themselves synthesized according to a methoddescribed in the literature (J. Org. Chem. (1968), 33 (1), 223-226).When X-—NR₃—CO— and R₃ is a linear or branched alkyl radical having from1 to 6 carbon atoms, the monoalkylamines can be obtained according to aprocess described in the literature (U.S. Pat. Nos. 3,208,859 and2,962,531). The non-commercial carboxylic acids of general formula (XI)can be accessed using methods described in the literature (Acta Chem.Scand. (1983), 37, 911-916; Synth. Commun. (1986), 16 (4), 479-483;Phophorus, Sulphur Silicon Relat. Elem. (1991), 62, 269-273).

When:

X=—Z₁—NR₃—CO—

and Y=—NH—Z₂—Q—, —NH—CO—Z₂—Q— with Q=O—Z₃—, R₃—N—Z₃— or S—Z₃—,

The ureas of general formula (II), diagram 5, in which A, X, Y and R₆are as defined above, are prepared by the addition of an amine ofgeneral formula (X) on an isocyanate of general formula (XII), (XIII) or(XIV) in a solvent such as chloroform at 20° C. Synthesis ofnon-commercial isocyanates of general formula (XII) is described in theliterature (J. Med. Chem. (1992), 35 (21), 3745-3754). The halogenatedintermediate ureas (XV) and (XVII) are then substituted by a derivativeof general formula (XVI), in which Q represents O—Z₃—, R₃—N—Z₃— orS—Z₃—, in the presence of a base such as, for example, K₂CO₃ or NaH inan aprotic solvent such as THF or DMF in order to finally obtain ureasof general formula (II).

When:

X=—Z₁—NH—CO—

and Y=piperazine, homopiperazine, 2-methylpiperazine,2,5-dimethylpiperazine, 4-aminopiperidine, —NR₃—Z₂—Q—, —NR₃—NH—CO—Z₂—,—NH—NH—Z₂—, —NR₃—O—Z₂—

The ureas of general formula (II), diagram 6, in which A, X, Y and R₆are as defined above, are prepared by the addition of an amine ofgeneral formula (VII), described previously, onto an isocyanate ofgeneral formula (XVIII) in the presence of a base such asdiisopropylethylamine.

The isocyanates of general formula (XVIII) are synthesized from primaryamines of general formula (X), described previously, triphosgene and atertiary amine (J. Org. Chem. (1994), 59 (7), 1937-1938).

The amines of general formula (VII) in which Y-—NH—O— are preparedaccording to a method described in the literature (J. Org. Chem. (1984),49 (8), 1348-1352).

When:

X=—Z₁—NR₃—CO—

and Y=—NR₃—SO₂—NR₃—Z₂—

The aminosulphonylureas of general formula (II), diagram 7, in which A,X, Y and R₆ are as defined above, are prepared by the addition of aminesof general formula (X), described previously, ontochlorosulphonylisocyanate (J. Med. Chem. (1996), 39 (6), 1243-1252). Theintermediate chlorosulphonylurea (XIX) is then condensed on the aminesof general formula (VII), described previously, in order to produce theaminosulphonylureas of general formula (II) which can optionally bealkylated by a halogenated derivative in the presence of a base such as,for example, NaH in order to produce derivatives of general formula(II).

When:

X=—Z₁—NR₃—SO₂—

and Y=—Z₂—Q—, with Q=O—Z₃—, R₃—N—Z₃— or S—Z₃—,

The sulphonamides of general formula (II), diagram 8, in which A, X, Yand R₆ are as defined above, are prepared by the addition of amines ofgeneral formula (X), described previously, onto halogenoalkylsulphonylchlorides of general formula (XX). The halogenoalkylsulphonamides ofgeneral formula (XXI), obtained intermediately, are then condensed on analcohol, an amine or a thiol of general formula (XVI) in the presence ofa base such as, for example, K₂CO₃ or NaH, in a polar solvent such as,for example, acetonitrile or DMF.

When:

X=—Z₁—NR₃—SO₂—

and Y=—NR₃—Z₂—Q—

The sulphamides of general formula (II), diagram 9, in which A, X, Y andR₆ are as defined above are prepared in three stages from amines ofgeneral formula (X) and chlorosulphonylisocyanate. The reaction of analcohol, such as tBuOH, on the isocyanate function ofchlorosulphonylisocyanate (Tetrahedron Lett. (1991), 32 (45), 6545-6546)leads to an intermediate of chlorosulphonylcarbamate type, which reactsin the presence of an amine of general formula (X) to produce aderivative of carboxylsulphamide type of general formula (XXII). Thetreatment of this intermediate in a strong acid medium produces thesulphamide derivative of general formula (XXIII). Alkylation of thecompounds of general formula (XXIII) by the halogenated derivatives ofgeneral formula (XXIV) in the presence of a base such as, for example,NaH in a polar aprotic solvent allows sulphamide derivatives of generalformula (II) to be obtained.

When:

X=—Z₁—NR₃—CO—and Y=—O—Z₂—Q—

The carbamates of general formula (II), diagram 10, in which A, X, Y andR₆ are as defined above, are prepared by the reaction of amines ofgeneral formula (X), described previously, with chloroformatederivatives of general formula (XXV) prepared according to a methoddescribed in the literature (Tetrahedron Lett. (1993), 34 (44),7129-7132).

When: X=—Z₁—CO—, —CH═CH—CO—

and Y=—O—Z₂—Q—

The esters of general formula (II), diagram 11, in which A, X, Y and R₆are as defined above, are prepared by the reaction of acids of generalformula (VIII) or (IX) and alcohols of general formula (XXVI) in thepresence de dicyclohexylcarbodiimide and of a catalytic quantity of4-dimethylaminopyridine in a solvent such as, for example, THF or DMF at20° C.

When:

X=—Z₁—

and Y=—O—CO—Z₂—Q—

The esters of general formula (II), diagram 12, in which A, X, Y and R₆are as defined above, can also be prepared by the reaction of acids ofgeneral formula (XI), described previously, with the alcohols of generalformula (V) under the conditions described previously.

When:

X=—Z₁—NR₃—CS—

and Y=—NH—Z₂—Q—, piperazine, homopiperazine, 2-methylpiperazine,2,5-dimethylpiperazine, 4-aminopiperidine, —NR₃—Z₂—Q—, —NH—NH—Z₂—,—NR₃—O—Z₂—

The thioureas of general formula (II) in which A, X, Y and R₆ are asdefined above, are prepared from the ureas described previously usingLawesson's reagent, following an experimental protocol described in theliterature (J. Med. Chem. (1995), 38 (18), 3558-3565).

When:

X represents a bond

Y=—O—Z₂—Q—, —S—Z₂—Q—

and Q=—HN—

The etheroxides or thioetheroxides of general formula (II), diagram 13,in which A, X, Y and R₆ are as defined above are prepared fromdihydroquinones of general formula (XXVII) (J. Chem. Soc., Perkin Trans.I, (1981), 303-306) or thiophenols of general formula (XXVIII) (Bio.Med. Chem. Letters, (1993), 3 (12), 2827-2830) and an electrophile (E⁺)such as, for example, bromoacetonitrile or 4-nitrophenyloxazolinone, inthe presence of K₂CO₃ (J. Heterocyclic Chem., (1994), 31, 1439-1443).The nitrites must be reduced (lithium hydride or catalytichydrogenation) in order to produce intermediates of general formula(XXIX) or (XXX). The opening of the nitrophenyloxazolinones, accessibleby reaction of the corresponding nitroanilines withchloroethylchloroformate as described in the literature (J. Am. Chem.Soc., (1953), 75, 4596), by phenols or thiophenols leads directly tocompounds of general formula (XXIX) or (XXX) which are then condensed onfluoronitrobenzene in order to produce intermediates of general formula(II).

When:

X represents —Z₁—CO— or —CH═CH—CO—

Y=—NR₃—CO—Q—

and Q=R₃—N—Z₃

The acylureas of general formula (II), diagram 14, in which A, X, Y andR₆ are as defined above are prepared by condensation of acids of generalformula (VIII) or (IX), diagram 3, and ureas of general formula (XXXI)in the presence of a coupling agent usually used in peptide synthesis,as described previously, in a solvent such as, for example,dichloromethane or DMF. The ureas of general formula (XXXI) areaccessible from isocyanates of general formula (XII), diagram 5,according to a method in the literature (J. Chem. Soc., Perkin Trans. 1,(1985), (1), 75-79).

Unless they are defined differently, all the technical and scientificterms used here have the same meaning as that usually understood by anordinary specialist in the field to which the invention belongs.Similarly, all publications, Patent Applications, Patents and otherreferences mentioned here are incorporated by way of reference.

The following examples are presented to illustrate the above proceduresand should in no way be considered as restricting the scope of theinvention.

EXAMPLES Example 13,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-{4-[(2-thienyl(imino)methyl)amino]phenyl}-benzamide hydrochloride: 1

1.1) 3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-(4-nitrophenyl)-benzamide:

1.38 g (10 mmoles) of 4-nitroaniline, 2.5 g (10 mmoles) of3,5-di-tert-butyl-4-hydroxybenzoic acid and 2.26 g (11 mmoles) ofdicyclohexylcarbodiimide are introduced into a 250 ml flask containing20 ml of THF. The reaction medium is agitated for 15 hours at ambienttemperature, and the precipitate which appears is filtered out andrinsed with ethyl acetate. After the solution is concentrated underreduced pressure, the residue is diluted in 20 ml of ethyl acetate andthe insoluble part is filtered out. The solvent is eliminated undervacuum and the residue is precipitated from diethyl ether. The solid isrecovered by filtration, rinsed abundantly with diethyl ether in orderto produce a white powder with a yield of 65%. Melting point: 277-278°C.

NMR ¹H (100 MHz, DMSO d6, δ): 10.72 (s, 1H, CONH); 8.30 (m, 4H, Ph-NO₂);7.80 (s, 2H, Ph); 1.60 (s, 18H, 2× tBu).

1.2) 3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-(4-aminophenyl)-benzamide:

In a 250 ml Parr flask, 2.4 g (6.5 mmoles) of3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-(4-nitrophenyl)-benzamide isdissolved in 50 ml of an absolute ethanol/dichloromethane mixture (1/1)in the presence of 10% Pd/C. The mixture is agitated under 20 PSI ofhydrogen, at 30° C., for one hour. After filtration on celite, thefiltrate is concentrated under vacuum. The evaporation residue is takenup in 25 ml of a 1M HCl solution. The precipitate formed is filtered andrinsed with 50 ml of diethyl ether followed by 50 ml of ethyl acetate.The amine is released from its salt by agitation in a mixture of 50 mlof ethyl acetate and 50 ml of 1M NaOH. After decanting, the organicphase is washed with 25 ml of 1M NaOH and 25 ml of brine. The organicsolution is dried over sodium sulphate, filtered, rinsed andconcentrated to dryness under reduced pressure to produce 1.09 g (49%)of a white powder. Melting point: 220-221° C.

NMR ¹H (100 MHz, DMSO d6, δ): 9.80 (s, 1H, CONH); 7.78 (s, 2H, Ph); 7.05(m, 4H, Ph-NH₂); 5.02 (s, 2H, OH); 1.60 (s, 18H, 2× tBu).

1.3) 3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-{4-[(2-thienyl(imino)methyl)-amino]phenyl}-benzamide hydrochloride: 1

880 mg (3.08 mmoles) of S-methyl-2-thiophenethiocarboximide hydriodide(Ann. Chim. (1962), 7, 303-337) is introduced into a 100 ml flaskcontaining a solution of 1.05 g (3.08 mmoles) of3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-(4-aminophenyl)-benzamide in 20ml of 2-propanol. After heating at 50° C. for 15 hours, the reactionmedium is concentrated to dryness under vacuum. The residue is taken upin 50 ml of ethyl acetate and 50 ml of a saturated solution of sodiumcarbonate. After decanting, the organic phase is washed successivelywith 50 ml of a saturated solution of sodium carbonate, 50 ml of waterand 50 ml of brine. The organic solution is dried over sodium sulphate,filtered and evaporated under reduced pressure. The crystals obtainedare taken up in diethyl ether, filtered and washed successively withethyl acetate and acetone. 0.77 g of base is obtained with a yield of58%.

The hydrochloride is prepared from 0.77 g (1.71 mmole) of base dissolvedin 60 ml of methanol and salified in the presence of 3.42 ml (3.42mmoles) of a molar solution of HCl in anhydrous diethyl ether. Afteragitating for 30 minutes at ambient temperature, the solvent isevaporated off under vacuum and the residue precipitated in the presenceof diethyl ether. The crystals obtained are filtered and rinsedabundantly with diethyl ether in order to finally produce after drying0.65 g (43%) of a pale yellow powder. Melting point: 290-291° C.

NMR ¹H (400 MHz, DMSO d6, δ): 11.55 (s, 1H, NH⁺); 10.40 (s, 1H, CONH);9.83 (s, 1H, NH⁺); 8.85 (s, 1H, NH⁺); 8.21 (m, 2H, thiophene); 7.70 (s,2H, Ph); 7.67 (m, 4H, Ph-NH); 7.60 (s, 1H, OH); 7.40 (m, 1H, thiophene);1.42 (s, 18H, 2× tBu). IR: ν_(OH): 3624 cm⁻¹, 3430 cm⁻¹; ν_(C═O)(amide): 1653 cm⁻¹; ν_(C═N) (amidine): 1587 cm⁻¹.

Example 23,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-{4-[[(2-thienyl-(imino)methyl)amino]phenyl]methyl}-benzamidehydrochloride: 2

2.1)3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-[(4-nitrophenyl)methyl]-benzamide:

1.88 g (10 mmoles) of p-nitrobenzylamine hydrochloride, 2.5 g (10mmoles) of 3,5-di-tert-butyl-4-hydroxybenzoic acid, 1.38 ml (10 mmoles)of triethylaamine and 2.26 g (11 mmoles) of dicyclohexylcarbodiimide areintroduced into a 250 ml flask containing 25 ml of THF. The reactionmedium is agitated for 15 hours at ambient temperature, the precipitatewhich appears is filtered out and rinsed with the minimum quantity ofethyl acetate. After concentration of the solution under reducedpressure, the residue is precipitated from a mixture of ethylacetate/diethyl ether (1/4) and filtered. The crystals are washedabundantly with diethyl ether in order to finally produce, after drying,a white powder with a yield of 74% (2.85 g). Melting point: 230-231° C.

NMR ¹H (100 MHz, CDCl₃, δ): 7.85 (m, 4H, Ph-NO₂); 7.69 (s, 2H, Ph); 6.82(m, 1H, NHCO); 5.67 (s, 1H, OH); 4.75 (d, 2H, CH₂—NHCO, J=6.5 Hz); 1.49(s, 18H, 2× tBu).

2.2)3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-[(4-aminophenyl)methyl]-benzamide:

In a 250 ml Parr flask, 2.85 g (7.4 mmoles) of3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-[(4-nitrophenyl)methyl]-benzamideis dissolved in 30 ml of an absolute ethanol/dichloromethane mixture(1/1) in the presence of 10% Pd/C. The mixture is agitated under 20 PSIof hydrogen, at 30° C., for one hour. After filtration on celite, thefiltrate is concentrated under vacuum. The evaporation residuecrystallizes spontaneously. It is left to rest overnight, the crystalsare filtered out and rinsed with a mixture of diethyl ether (45 ml) andacetone (5 ml). 1.63 g (62%) of a white powder is obtained. Meltingpoint: 188-189° C.

NMR ¹H (100 MHz, CDCl₃, δ): 7.62 (s, 2H, Ph); 6.95 (m, 4H, Ph-NH₂); 6.20(m, 1H, NHCO); 5.58 (s, 1H, OH); 4.50 (d, 2H, CH₂—NHCO, J=6.5 Hz); 3.70(wide s, 2H, NH₂); 1.47 (s, 18H, 2× tBu).

2.3)3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-{4-[[(2-thienyl-(imino)methyl)-amino]phenyl]methyl}-benzamidehydrochloride: 2

The experimental protocol used is the same as that described forcompound 1, with3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-[(4-aminophenyl)methyl]-benzamidereplacing the3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-(4-aminophenyl)-benzamide. Aftersalification with a molar solution of HCl in anhydrous diethyl ether, awhite powder is obtained with a yield of 56%. Melting point: 218-219° C.

NMR ¹H (400 MHz, DMSO d6, δ): 11.60 (s, 1H, NH⁺); 9.83 (s, 1H, NH⁺);9.02 (s, 1H, CONH); 8.90 (s, 1H, NH⁺); 8.18 (m, 2H, thiophene); 7.70 (s,2H, Ph); 7.42 (m, 6H, thiophene, Ph-NH, OH); 4.50 (d, 2H, CH₂—NHCO,J=5.7 Hz); 1.40 (s, 18H, 2× tBu). IR: ν_(OH): 3624 cm⁻¹, 3424 cm⁻¹;ν_(C═O) (amide): 1644 cm⁻¹; ν_(C═N) (amidine): 1568 cm⁻¹.

Example 34-acetoxy-3,5-dimethoxy-N-{4-[[(2-thienyl(imino)methyl)amino]phenyl]methyl}-benzamide:3

3.1) 4-acetoxy-3,5-dimethoxy-benzoic acid:

In a 100 ml flask, under a nitrogen atmosphere, 1.50 g (7.57 mmoles) ofsyringic acid is dissolved in 15 ml of dry pyridine. 0.86 ml (9.08mmoles) of acetic anhydride is added dropwise and the mixture isagitated at ambient temperature for 18 hours. The pyridine is evaporatedoff under reduced pressure, the residue is taken up in 25 ml ofdichloromethane and washed with 10 ml of a molar solution of HCl thenwith 2×10 ml of water. The organic phase is dried over sodium sulphate,filtered and evaporated under vacuum. 1.72 g (95%) of a beige powder isobtained. Melting point: 181-183° C.

NMR ¹H (100 MHz, CDCl₃, δ): 8.15 (s, 1H, CO₂H); 7.40 (s, 2H, Ph); 3.90(s, 6H, 2× OCH₃); 2.40 (s, 3H, CH₃).

3.2) 4-acetoxy-3,5-dimethoxy-N-[(4-nitrophenyl)methyl]-benzamide:

The experimental protocol used is the same as that described forintermediate 2.1, 4-acetoxy-3,5-dimethoxy-benzoic acid replacing the3,5-di-tert-butyl-4-hydroxy-benzoic acid. A colourless oil is obtainedwith a yield of 28%.

NMR ¹H (100 MHz, DMSO d6, δ): 9.26 (t, 1H, NHCO, J=6.0 Hz); 7.91 (m, 4H,Ph-NO₂); 7.31 (s, 2H, Ph); 4.65 (d, 2H, CH₂, J=6.0 Hz); 3.83 (s, 6H, 2×OCH₃); 2.28 (s, 3H, CH₃).

3.3) 4-acetoxy-3,5-dimethoxy-N-[(4-aminophenyl)methyl]-benzamide:

The experimental protocol used is the same as that described forintermediate 2.2,4-acetoxy-3,5-dimethoxy-N-[(4-nitrophenyl)methyl]-benzamide replacingthe3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-[(4-nitrophenyl)methyl]-benzamide.A colourless oil is obtained with a yield of 82%. The product is useddirectly in the following stage without additional purification.

3.4) 4-acetoxy-3,5-dimethoxy-N-{4-[[(2-thienyl(imino)methyl)amino]phenyl]methyl}-benzamide: 3

The experimental protocol used is the same as that described forcompound 1, with4-acetoxy-3,5-dimethoxy-N-[(4-aminophenyl)methyl]-benzamide replacingthe 3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-(4-aminophenyl)-benzamide.The base 3 in the form of a beige powder is obtained with a yield of65%. Melting point: 47-48° C.

NMR ¹H (400 MHz, DMSO d6, δ): 9.08 (wide s, 1H, CONH); 7.75 (m, 1H,thiophene); 7.62 (m, 1H, thiophene); 7.30 (s, 2H, Ph); 7.10 (m, 1H,thiophene); 5 7.07 (m, 4H, Ph-N); 6.48 (wide s, 2H, NH₂); 4.50 (d, 2H,CH₂, J=4.6 Hz); 3.80 (s, 6H, 2× OCH₃); 2.30 (s, 3H, CH₃). IR: ν_(C═O)(ester): 1760 cm⁻¹; ν_(C═O) (amide): 1630 cm⁻¹; ν_(C═N) (amidine): 1540cm⁻¹.

Example 43,5-dimethoxy-4-hydroxy-N-{4[[(2-thienyl(imino)methyl)amino]phenyl]methyl}-benzamide:4

In a 50 ml flask, 1 ml (2 mmoles) of 2N hydrochloric acid is introduceddropwise into a solution of 0.59 g (1 mmole) of compound 3 in 5 ml ofethanol. The reaction medium is agitated for 18 hours at 50° C. Thesolvents are evaporated to dryness, the residue is taken up indichloromethane (5 ml) and washed with molar soda solution (3×5 ml).After drying the organic phase, filtration and concentration to drynessis carried out and the oil obtained is purified by chromatography on asilica gel column (eluant: dichloromethane/methanol: 9/1). The purefractions are collected and after evaporation under vacuum a beigepowder is obtained with a yield of 60%. Melting point 55-58° C.

NMR ¹H (400 MHz, DMSO d6, δ): 8.92 (s, 1H, OH); 8.84 (m, 1H, CONH); 7.75(m, 1H, thiophene); 7.63 (m, 1H, thiophene); 7.26 (s, 2H, Ph); 7.10 (m,1H, thiophene); 7.05 (m, 4H, Ph-N); 6.50 (s, 2H, NH₂); 4.45 (d, 2H, CH₂,J=5.7 Hz); 3.81 (s, 6H, 2× OCH₃). IR: ν_(OH): 3300 cm⁻¹; ν_(C═O)(amide): 1630 cm⁻¹; ν_(C═N) (amidine): 1590 cm⁻¹.

Example 53,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-{4-[2-[(2-thienyl-(imino)methyl)amino]phenyl]ethyl}-benzamidehydriodide: 5

5.1)3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-[2-(4-nitrophenyl)ethyl]-benzamide:

2.02 g (10 mmoles) of 4-nitrophenetylamine hydrochloride, 2.5 g (10mmoles) of 3,5-di-tert-butyl-4-hydroxy-benzoic acid, 1.38 ml (10 mmoles)of triethylamine and 2.26 g (11 mmoles) of dicyclohexylcarbodiimide areintroduced into a 100 ml flask containing 20 ml of THF. The reactionmedium is agitated for 15 hours at ambient temperature, the precipitatewhich appears is filtered out and rinsed with ethyl acetate. Afterconcentration of the filtrate under reduced pressure, the residue isprecipitated from diethyl ether. The solid is recovered by filtrationand rinsed with diethyl ether. A white powder is obtained with a yieldof 73%. Melting point: 204-206° C.

NMR ¹H (100 MHz, CDCl₃, δ): 7.52 (s, 2H, Ph); 6.85 (m, 4H, Ph-NO₂); 6.02(m, 1H, NHCO); 3.62 (m, 2H, CH₂—NHCO); 2.82 (m, 2H, CH₂-Ph-NO₂); 1.48(s, 18H, 2× tBu).

5.2)3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-[2-(4-aminophenyl)ethyl]-benzamide:

The experimental protocol used is the same as that described forintermediate 2.2,3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-[2-(4-nitrophenyl)ethyl]-benzamidereplacing the3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-[(4-nitrophenyl)methyl]-benzamide.A white powder is obtained with a yield of 76%. Melting point: 193-195°C.

NMR ¹H (100 MHz, CDCl₃, δ): 7.80 (m, 4H, Ph-NH₂); 7.55 (s, 2H, Ph); 6.10(m, 1H, NHCO); 5.55 (s, 1H, OH); 3.75 (m, 2H, CH₂—NHCO); 3.10 (m, 2H,CH₂-Ph-NH₂); 1.50 (s, 18H, 2× tBu).

5.3)3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-{4-[2-[(2-thienyl(imino)methyl)-amino]phenyl]ethyl}-benzamidehydriodide: 5

0.78 g (2.74 mmoles) of S-methyl-2-thiophene-thiocarboximide hydriodide(Ann. Chim. (1962), 7, 303-337) is introduced into a 50 ml flaskcontaining 1.01 g (2.74 mmoles) of3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-[2-(4-aminophenyl)ethyl]-benzamidedissolved in 20 ml of 2-propanol. The reaction medium is heated at 40°C. for 4 hours. The solvent is evaporated off under vacuum and theresidue is precipitated in the presence of 50 ml of a water/ethylacetate mixture (1/1). The crystals formed are filtered out and washedsuccessively with ethyl acetate and diethyl ether. After drying, a paleyellow powder is obtained with a yield of 68%. Melting point: 185-186°C.

NMR ¹H (400 MHz, DMSO d6, δ): 9.80 (s, 1H, NH⁺); 8.88 (s, 1H, NH⁺); 8.40(s, 1H, CONH); 8.12 (m, 2H, thiophene); 7.60 (s, 2H, Ph); 7.42 (m, 6H,thiophene, Ph-NH, OH); 3.52 (d, 2H, CH₂—NHCO, J=5.9 Hz); 2.90 (m, 2H,CH₂-Ph-NH); 1.40 (s, 18H, 2× tBu). IR: ν_(OH): 3624 cm⁻¹, 3423 cm⁻¹;ν_(C═O) (amide): 1636 cm⁻¹; ν_(C═N) (amidine): 1569 cm⁻¹.

Example 64-acetoxy-3,5-dimethoxy-N-{4-[2-[(2-thienyl(imino)methyl)-amino]phenyl]ethyl}-benzamidefumarate: 6

6.1) 4-acetoxy-3,5-dimethoxy-N-[2-(4-nitrophenyl)ethyl]-benzamide:

The experimental protocol used is the same as that described forintermediate 5.1, with 4-acetoxy-3,5-dimethoxy-benzoic acid(intermediate 3.1) replacing the 3,5-di-tert-butyl-4-hydroxy benzoicacid. A colourless oil is obtained with a yield of 70%. The product isused directly in the following stage.

6.2) 4-acetoxy-3,5-dimethoxy-N-[2-(4-aminophenyl)ethyl]-benzamide:

The experimental protocol used is the same as that described forintermediate 2.2, with4-acetoxy-3,5-dimethoxy-N-[2-(4-nitrophenyl)ethyl]-benzamide replacingthe3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-[(4-nitrophenyl)methyl]-benzamide.A colourless oil is obtained with a quantitative yield. The product isused directly in the following stage without additional purification.

6.3)4-acetoxy-3,5-dimethoxy-N-{4-[2-[(2-thienyl(imino)methyl)amino]-phenyl]ethyl}-benzamidefumarate: 6

The experimental protocol used to produce the free base is the same asthat described for the synthesis of compound 1, with4-acetoxy-3,5-dimethoxy-N-[2-(4-aminophenyl)ethyl]-benzamide replacingthe 3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-(4-aminophenyl)-benzamide.

The product of the reaction is salified in the presence of an equimolarquantity of fumaric acid in ethanol under reflux. Compound 6 is obtainedin the form of a beige powder with a yield of 74%. Melting point:178-180° C.

NMR ¹H (400 MHz, DMSO d6, δ): 8.60 (m, 1H, CONH); 7.75 (m, 1H,thiophene); 7.64 (d, 1H, thiophene, J=5.0 Hz); 7.20 (s, 2H, Ph); 7.11(t, 1H, thiophene, J=9.0 Hz); 7.02 (m, 4H, Ph-N); 6.61 (s, 2H, CH═CHfumarate); 3.81 (s, 6H, 2× OCH₃); 3.50 (q, 2H, CH₂—N, J=6.5 Hz); 2.82(t, CH₂-Ph, J=7.0 Hz); 2.27 (s, 3H, CH₃). IR: ν_(C═O) (ester): 1750cm⁻¹; ν_(C═O) (amide): 1640 cm⁻¹; ν_(C═N) (amidine): 1550 cm⁻¹.

Example 73,5-dimethoxy-4-hydroxy-N-{4-[2-[(2-thienyl-(imino)methyl)-amino]phenyl]ethyl}-benzamidehydrochloride: 7

In a 50 ml flask, 1.40 ml (2.80 mmoles) of a solution of 2N hydrochloricacid is added dropwise to a solution of 0.64 g (1.37 mmoles) of compound6 in the form of the free base in 5 ml of ethanol. The reaction mediumis agitated for 18 hours at 50° C. The solvents are evaporated todryness and the evaporation residue is precipitated from a mixture of 5ml of a 2N solution of soda and 10 ml of dichloromethane. Afterfiltration, the solid is taken up in (4N) hydrochloric ethanol. A lightprecipitate is then eliminated. The solvent is evaporated under reducedpressure and the residue taken up in acetone. Product 7 precipitated inthe form of the hydrochloride is obtained with a yield of 58%. Meltingpoint: 164-167° C.

NMR ¹H (400 MHz, DMSO d6, δ): 9.80 (wide s, 1H, NH⁺); 8.90 (s, 2H, NH⁺,OH); 8.54 (m, 1H, CONH); 8.18 (s, 1H, thiophene); 8.16 (s, 1H,thiophene); 7.40 (m, 4H, Ph-N); 7.21 (s, 2H, Ph); 7.11 (m, 1H,thiophene); 3.81 (s, 6H, 2× OCH₃); 3.51 (q, 2H, CH₂—N, J=7.0 Hz); 2.92(t, CH₂-Ph, J=7.0 Hz).

IR: ν_(OH): 3300 cm⁻¹; ν_(C═O) (amide): 1620 cm⁻¹; ν_(C═N) (amidine):1560 cm⁻¹.

Example 83,4,5-trihydroxy-N-{4-[2-[(2-thienyl(imino)methyl)-amino]phenyl]ethyl}-benzamidehemi-fumarate: 8

8.1) 3,4,5-trihydroxy-N-[2-(4-nitrophenyl)ethyl]-benzamide:

2 g (11.5 mmoles) of gallic acid, 2.5 g (11.5 mmoles) of4-nitrophenetylamine hydrochloride, 1.8 g (11.5 mmoles) of hydrated1-hydroxybenzotriazole, 2.25 g (11.5 mmoles) of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 3.3 ml(23 mmoles) of triethylamine are introduced into a 100 ml flaskcontaining 30 ml of anhydrous DMF. The orange-coloured solution obtainedis agitated at 20° C. for 20 hours and diluted in a mixture ofdichloromethane (50 ml) and water (30 ml). After decanting, the organicphase is washed with a molar solution of hydrochloric acid (20 ml) andwith water (3×20 ml) until neutrality is achieved. After drying theorganic phase over magnesium sulphate, followed by filtration andconcentration under vacuum, the residue is purified on a silica gelcolumn (eluant: dichloromethane/methanol: 9/1). The expected product isobtained in the form of a colourless oil with a yield of 42% (1.57 g).

NMR ¹H (100 MHz, DMSO d6, δ): 8.95 (m, 3H, 3× OH); 7.85 (m, 4H, Ph-NO₂);6.80 (s, 2H, Ph); 3.36 (m, 2H, CH₂-N); 2.97 (t, 2H, CH₂-Ph, J=6.0 Hz).

8.2) 3,4,5-trihydroxy-N-[2-(4-aminophenyl)ethyl]-benzamide:

The experimental protocol used is the same as that described forintermediate 2.2, with3,4,5-trihydroxy-N-[2-(4-nitrophenyl)ethyl]-benzamide replacing the3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-[(4-nitrophenyl)methyl]-benzamide.A beige powder is obtained with a yield of 89%. Melting point: 167-169°C.

NMR ¹H (100 MHz, DMSO d6, δ): 8.80 (m, 3H, OH); 8.07 (t, 1H, NHCO, J=5.0Hz); 6.81 (s, 2H, Ph); 6.68 (m, 4H, Ph-NH₂); 3.28 (m, 2H, CH₂-N); 2.60(t, 2H, CH₂-Ph, J=7.0 Hz).

8.3)3,4,5-trihydroxy-N-{4-[2-[(2-thienyl(imino)methyl)amino]-phenyl]ethyl}-benzamidehemi-fumarate: 8

The experimental protocol used is the same as that described forcompound 1, with 3,4,5-trihydroxy-N-[2-(4-aminophenyl)ethyl]-benzamidereplacing the3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-(4-aminophenyl)-benzamide. Base8 is obtained in the form of a powder which is salified, by heatingunder reflux with ethanol, in the presence of one equivalent of fumaricacid. The salt crystallizes spontaneously at 20° C. After filtration andwashing with ethanol the expected product is obtained in the form of abeige powder with a yield of 53%. Melting point: 245-246° C.

NMR ¹H (400 MHz, DMSO d6, δ): 8.85 (m, 3H, 3× OH); 8.14 (t, 1H, NHCO,J=5.0 Hz); 7.73 (s, 1H, thiophene); 7.60 (d, 1H, thiophene, J=5.0 Hz);7.16 (s, 2H, Ph); 7.09 (t, 1H, thiophene, J=4.0 Hz); 6.80 (m, 4H, Ph-N);6.59 (wide s, 2H, ½—CH═CH, NH); 3.41 (m, 3H, CH₂—N⁺NH); 2.76 (t, 2H,CH₂, J=7.5 Hz). IR: ν_(OH): 3300 cm⁻¹; ν_(C═O) (amide): 1620 cm⁻¹;ν_(C═N) (amidine): 1590 cm⁻¹.

Example 9N-{4-[4-[3,5-bis-(1,1-dimethylethyl)-4-hydroxybenzoyl]-1-piperazinyl]phenyl}-2-thiophenecarboximidamidehydrochloride: 9

9.1)2,6-bis-(1,1-dimethylethyl)-4-{[4-(4-nitrophenyl)-1-piperazinyl]-carbonyl}-phenol:

2.07 g (10 mmoles) of 1-(4-nitrophenyl)piperazine, 2.5 g (10 mmoles) of3,5-di-tert-butyl-4-hydroxybenzoic acid and 2.26 g (11 mmoles) ofdicyclohexylcarbodiimide are introduced into a 100 ml flask containing25 ml of DMF. The reaction medium is agitated for 15 hours at ambienttemperature, the precipitate which appears is filtered out and rinsedwith ethyl acetate. After concentration of the filtrate under reducedpressure, the residue is diluted in 20 ml of ethyl acetate and a newinsoluble is eliminated by filtration. The solvent is evaporated offunder vacuum and the residue is precipitated from diethyl ether. Thesolid is filtered, rinsed with 2×20 ml of ethyl acetate in order toobtain a yellow powder with a yield of 89%. Melting point: 159.5-160.5°C.

NMR ¹H (100 MHz, CDCl₃, δ): 7.58 (m, 4H, Ph-NO₂); 7.30 (s, 2H, Ph); 5.50(s, 1H, OH); 3.85 (m, 4H, piperazine); 3.55 (m, 4H, piperazine); 1.46(s, 18H, 2× tBu).

9.2)2,6-bis-(1,1-dimethylethyl)-4-{[4-(4-aminophenyl)-1-piperazinyl]-carbonyl}-phenol:

In a 250 ml Parr flask, 2.19 g (5.0 mmoles) of intermediate 9.1 isdissolved in 50 ml of absolute ethanol in the presence of 10% Pd/C. Themixture is agitated under 20 PSI of hydrogen, at 30° C., for one hour.After filtration on celite, the filtrate is concentrated under vacuum.The evaporation residue is taken up in 25 ml of diethyl ether, filteredand rinsed with 2×20 ml of diethyl ether. A pale pink powder is obtainedwith a yield of 82%. Melting point: 221-222° C.

NMR¹H (100 MHz, CDCl₃, δ): 7.30 (s, 2H, Ph); 6.75 (m, 4H, Ph-NH₂); 5.45(s, 1H, OH); 3.80 (m, 4H, piperazine); 3.10 (m, 4H, piperazine); 1.49(s, 18H, 2× tBu).

9.3)N-{4-[4-[3,5-bis-(1,1-dimethylethyl)-4-hydroxybenzoyl]-1-piperazinyl]-phenyl}-2-thiophenecarboximidamidehydrochloride: 9

The experimental protocol used is the same as that described forcompound 1, with2,6-bis-(1,1-dimethylethyl)-4-{[4-(4-aminophenyl)-1-piperazinyl]-carbonyl}-phenolreplacing the3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-(4-aminophenyl)-benzamide. Aftertreatment with a molar solution of HCl in anhydrous diethyl ether, abeige powder is obtained with a yield of 75%. Melting point: 235-236° C.

NMR ¹H (400 MHz, DMSO d6, δ): 11.45 (s, 1H, NH⁺); 9.78 (s, 1H, NH⁺);8.75 (s, 1H, NH⁺); 8.19 (m, 2H, thiophene); 7.29 (m, 5H, Ph-N,thiophene); 7.10 (s, 2H, Ph); 5.60 (wide s, 1H, OH); 3.70 (m, 4H,piperazine); 3.30 (m, 4H, piperazine); 1.40 (s, 18H, 2× tBu). IR:ν_(OH): 3633 cm⁻¹, 3433 cm⁻¹, ν_(C═O) (amide): 1617 cm⁻¹; ν_(C═N)(amidine): 1590 cm⁻¹.

Example 10N-{4-[4-[3,5-bis-(1,1-dimethylethyl)-4-hydroxybenzyl]-1-piperazinyl]phenyl}-2-thiophenecarboximidamidehydrochloride: 10

10.1) 2,6-bis-(1,1-dimethylethyl)-4-bromomethylphenol:

In a 250 ml three-necked flask under a nitrogen atmosphere, 2.36 g (10mmoles) of 3,5 di-tert-butyl-4-hydroxybenzylic alcohol is dissolved in25 ml of anhydrous THF. The solution is cooled down using an ice bathbefore the dropwise addition of 0.95 ml (10 mmoles) of phosphorustribromide diluted with 25 ml of anhydrous THF. After 15 minutes ofagitation at 0° C., the solution is diluted with 100 ml ofdichloromethane and washed with 3×30 ml of water followed by 30 ml ofbrine. The organic phase is dried over sodium sulphate, filtered andconcentrated under vacuum to produce a brown oil which is used directlyin the following stage.

10.2)2,6-bis-(1,1-dimethylethyl)-4-{[4-(4-nitrophenyl)-1-piperazinyl]-methyl}-phenol:

In a 100 ml flask containing a solution of 2.99 g (10 mmoles) of2,6-bis-(1,1-dimethylethyl)-4-bromomethylphenol in 30 ml of DMF, 1.38 g(10 mmoles) of potassium carbonate and 2.07 g (10 mmoles) of1-(4-nitrophenyl)piperazine are added successively. After agitation fortwo hours at ambient temperature, the reaction medium is diluted with150 ml of dichloromethane and washed successively with 3×40 ml of waterfollowed by 40 ml of brine. The organic solution is dried over sodiumsulphate, filtered and concentrated under reduced pressure. The brownresidue obtained is purified on a silica gel column (eluant: petroleumether (B.p. 40-70° C.)/ethyl acetate: 8/2). After concentration of thepure fractions, 2.31 g (54%) of a brown powder is obtained. Meltingpoint: 177.5-178.5° C.

NMR ¹H (100 MHz, CDCl₃, δ): 7.50 (m, 4H, Ph-NO₂); 7.12 (s, 2H, Ph); 5.19(s, 1H, OH); 3.50 (s, 2H, CH₂-Ph); 3.49 (m, 4H, piperazine); 2.60 (m,4H, piperazine); 1.49 (s, 18H, 2× tBu).

10.3)2,6-bis-(1,1-dimethylethyl)-4-{[4-(4-aminophenyl)-1-piperazinyl]-methyl}-phenol:

The experimental protocol used is the same as that described forintermediate 9.2, with2,6-bis-(1,1-dimethylethyl)-4-{[[4-(4-nitrophenyl)-1-piperazinyl]-carbonyl]-methyl}-phenolreplacing the2,6-bis-(1,1-dimethylethyl)-4-{[4-(4-nitrophenyl)-1-piperazinyl]-carbonyl)}-phenol.A pale pink powder is obtained with a yield of 75%. Melting point:152-154° C.

NMR ¹H (100 MHz, CDCl₃, δ): 7.12 (s, 2H, Ph); 6.78 (m, 4H, Ph-NH₂); 3.59(s, 2H, CH₂-Ph); 3.18 (m, 4H, piperazine); 2.70 (m, 4H, piperazine);1.47 (s, 18H, 2× tBu).

10.4)N-{4-[4-[3,5-bis-(1,1-dimethylethyl)-4-hydroxybenzyl]-1-piperazinyl]-phenyl}-2-thiophenecarboximidamidehydrochloride: 10

0.43 g (1.5 mmole) of S-methyl-2-thiophene-thiocarboximide hydriodide(Ann. Chim. (1962), 7, 303-337) is introduced into a 100 ml flaskcontaining 0.59 g (1.5 mmole) of intermediate 10.3 in 20 ml of2-propanol. After heating under reflux for 15 hours, the reaction mediumis concentrated to dryness under vacuum. The residue is purified on asilica gel column (eluant: dichloromethane/ethanol: 90/10). The purefractions are concentrated under vacuum and the evaporation residue issalified in the presence of a molar solution of HCl in anhydrous diethylether. A pale yellow powder is obtained with a yield of 40%. Meltingpoint: 234-236° C.

NMR ¹H (400 MHz, DMSO d6, δ): 11.60 (s, 1H, NH⁺); 11.40 (s, 1H, NH⁺);9.75 (s, 1H, NH⁺); 8.70 (s, 1H, NH⁺); 8.17 (m, 2H, thiophene); 7.39 (s,2H, Ph); 7.38 (m, 1H, thiophene); 7.24 (m, 5H, Ph-N, OH); 4.26 (d, 2H,CH₂-Ph, J=4.6 Hz); 3.90 (m, 2H, piperazine); 3.35 (m, 4H, piperazine);3.15 (m, 2H, piperazine); 1.41 (s, 18H, 2× tBu). IR: ν_(OH): 3624 cm⁻¹,3418 cm⁻¹; ν_(C═N) (amidine): 1610 cm⁻¹.

Example 11N-{4-[4-[3,5-dimethoxy-4-hydroxybenzoyl]-1-piperazinyl]-phenyl}-2-thiophenecarboximidamidehydrochloride: 11

11.1)2,6-dimethoxy-4-{[4-(4-nitrophenyl)-1-piperazinyl]carbonyl}-phenol:

In a 100 ml flask, 0.99 g (5 mmoles) of syringic acid, 0.74 g (5.5mmoles) of hydroxybenzotriazol, 1.10 g (5.5 mmoles) ofdicyclohexylcarbodiimide and 1.04 g (5 mmoles) of1-(4-nitrophenyl)piperazine are dissolved in 10 ml of DMF. Afteragitation at ambient temperature for 7 hours, the mixture is filteredand the precipitate rinsed with 20 ml of DMF followed by 100 ml ofchloroform. 2 g of a yellow powder is obtained, containing approximately20% of dicyclohexylurea. The product is used as it is in the followingstage.

NMR ¹H (100 MHz, DMSO d6, δ): 7.69 (m, 4H, Ph-NO₂); 6.88 (s, 2H, Ph);5.72 (m, 1H, OH); 3.91 (s, 6H, 2× OCH₃); 3.75 (m, 4H, piperazine); 3.49(m, 4H, piperazine).

11.2)2,6-dimethoxy-4-{[4-(4-aminophenyl)-1-piperazinyl]carbonyl}-phenol:

In a 250 ml Parr flask, 2 g of intermediate 11.1 is dissolved in 40 mlof absolute ethanol/DMSO (1/3) in the presence of 10% Pd/C. The mixtureis agitated under 20 PSI of hydrogen, at 25° C., for 15 hours. Afterfiltration on celite, the filtrate is concentrated under vacuum. Thebrown evaporation residue is taken up in 50 ml of ethyl acetate, theprecipitate formed is eliminated by filtration, rinsed with 20 ml ofethyl acetate and the filtrate extracted with 2×25 ml of a molarsolution of HCl. The aqueous phase is alkalinized by the addition ofpowdered sodium carbonate and extracted with 2×50 ml of ethyl acetate.The organic solution is dried over sodium sulphate, filtered andconcentrated under vacuum. The powder obtained is taken up in 20 ml ofdiethyl ether containing 3 ml of methanol, filtered and rinsed usingdiethyl ether. 400 mg (22% over the two stages) of brown crystals areobtained. Melting point: 182-183° C.

NMR ¹H (100 MHz, DMSO d6, δ): 6.80 (s, 2H, Ph); 6.74 (m, 4H, Ph-NH₂);4.80 (m, 2H, NH₂); 3.91 (s, 6H, 2× OCH₃); 3.77 (m, 4H, piperazine); 3.08(m, 4H, piperazine).

11.3)N-{4-[4-[3,5-dimethoxy-4-hydroxybenzoyl]-1-piperazinyl]-phenyl}-2-thiophenecarboximidamidehydrochloride: 11

0.32 g (1.13 mmole) of S-methyl-2-thiophenethiocarboximide hydriodide(Ann. Chim. (1962), 7, 303-337) is introduced into a 100 ml flaskcontaining a solution of 0.4 g (1.13 mmole) of intermediate 11.2 in 10ml of 2-propanol. After heating at 50° C. for 15 hours, the reactionmedium is concentrated to dryness under vacuum. The evaporation residueis then taken up in 100 ml of an ethyl acetate/saturated solution ofsodium carbonate mixture (1/1). A precipitate appears which is filteredand rinsed successively with 20 ml of water, 20 ml of ethyl acetate and50 ml of ether. The base obtained is salified in the presence of a molarsolution of HCl in anhydrous diethyl ether. After filtration, rinsingwith 10 ml of acetone and drying, 0.12 g (20%) of a pale yellow powderis obtained. Melting point: 184-185° C.

NMR ¹H (400 MHz, DMSO d6, δ): 11.47 (s, 1H, NH⁺); 9.78 (s, 1H, NH⁺);8.76 (s, 1H, NH⁺); 8.18 (m, 2H, thiophene); 7.37 (m, 1H, thiophene);7.28 (m, 4H, Ph-N); 6.74 (s, 2H, Ph); 4.27 (wide s, 1H, OH); 3.80 (s,6H, 2× OCH₃); 3.70 (m, 4H, piperazine); 3.33 (m, 4H, piperazine). IR:ν_(OH): 3423 cm⁻¹; ν_(C═O) (amide): 1610 cm⁻¹; ν_(C═N) (amidine): 1587cm⁻¹.

Example 12 3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-N-{4-[(2-thienyl(imino)methyl)amino]phenyl}-2H-1-benzopyran-2-carboxamide hydrochloride:12

12.1)3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-N-(4-nitrophenyl)-2H-1-benzopyran-2-carboxamide:

In a 100 ml flask, 1.62 g (10 mmoles) of 1.1′-carbonyl-diimidazol isadded to a solution of 2.5 g (10 mmoles) of Trolox® in 25 ml of THF.After agitation at ambient temperature for one hour, a solution of4-nitroaniline in 20 ml of THF is added dropwise. Agitation is continuedfor 15 hours and the solvent is evaporated off under vacuum. The residueis diluted in 50 ml of dichloromethane and washed successively with 25ml of a molar solution of hydrochloric acid, 25 ml of water and 25 ml ofbrine. The organic phase is dried over sodium sulphate, filtered andconcentrated under reduced pressure. The oil obtained is purified on asilica gel column (eluant: petroleum ether (B.p. 40-70° C.)/ethylacetate: 7/3). After concentration of the pure fractions, a pale yellowpowder is obtained with a yield of 77%. Melting point: 150-151° C.

NMR ¹H (100 MHz, CDCl₃, δ): 8.68 (s, 1H, CONH); 7.91 (m, 4H, Ph); 4.59(s, 1H, OH); 2.95-0.87 (m, 16H, Trolox®).

12.2)3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-N-(4-aminophenyl)-2H-1-benzopyran-2-carboxamide:

The experimental protocol used is the same as that described forintermediate 9.2, with3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-N-(4-nitrophenyl)-2H-1-benzopyran-2-carboxamidereplacing the2,6-bis-(1,1-dimethylethyl)-4-{[4-(4-nitrophenyl)-1-piperazinyl]-carbonyl}-phenol.The product of the reaction is purified on a silica gel column (eluant:petroleum ether (B.p. 40-70° C.)/ethyl acetate: 6/4). The pure fractionsare collected, after evaporation of the solvent under vacuum, acolourless oil is obtained with a yield of 45%.

NMR ¹H (100 MHz, CDCl₃, δ): 8.19 (s,1H, CONH); 7.00 (m, 4H, Ph); 4.59(s, 1H, OH); 3.65 (wide s, 2H, NH₂); 2.95-0.87 (m, 16H, Trolox®).

12.3) 3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-N-{4-[2-thienyl(iminomethyl)amino]phenyl}-2H-1-benzopyran-2-carboxamide hydrochloride:12

The experimental protocol used is the same as that described forcompound 1, with3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-N-(4-aminophenyl)-2H-1-benzopyran-2-carboxamidereplacing the3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-(4-aminophenyl)-benzamide.Melting point: 279-280° C.

NMR ¹H (400 MHz, DMSO d6, δ): 9.80 (s, 1H, NH⁺); 9.50 (s, 1H, NH⁺); 8.73(s, 1H, NHCO); 8.18 (m, 2H, thiophene); 7.60 (s, 1H, OH); 7.59 (m, 4H,Ph); 7.36 (m, 1H, thiophene); 2.60-1.57 (m, 16H, Trolox®). IR: ν_(OH):3236 cm⁻¹; ν_(C═O) (amide): 1683 cm⁻¹; ν_(C═N) (amidine): 1577 cm⁻¹.

Example 13N-{4-[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)-carbonyl]-1-piperazinyl]phenyl}-2-thiophenecarboximidamidehydrochloride: 13

13.1)3,4-dihydro-2,5,7,8-tetramethyl-2-{4-[(4-nitrophenyl)-1-piperazinyl]-carbonyl}-2H-1-benzopyran-6-ol:

In a 100 ml flask, 1.62 g (10 mmoles) of 1.1′-carbonyl-diimidazole isadded to a solution of 2.5 g (10 mmoles) of Trolox® in 25 ml of THF.After one hour of agitation at ambient temperature, a solution of1-(4-nitrophenyl)piperazine in 10 ml of DMF is added dropwise. Agitationis continued for 15 hours, the reaction medium is then concentratedunder vacuum. The evaporation residue is dissolved in 50 ml ofdichloromethane and washed successively with 3×25 ml of water and 25 mlof brine. The organic phase is dried over sodium sulphate, filtered andconcentrated under reduced pressure. The oil obtained is precipitatedfrom 30 ml of a (95/5) ethyl acetate/methanol mixture, the solid isfiltered out and washed with 2×20 ml of ethyl acetate. A pale yellowpowder is obtained with a yield of 79%. Melting point: 199-200° C.

NMR ¹H (100 MHz, CDCl₃, δ): 7.45 (m, 4H, Ph); 4.41-3.35 (m, 8H,piperazine); 2.95-1.25 (m, 16H, Trolox®).

13.2)3,4-dihydro-2,5,7,8-tetramethyl-2-{4-[(4-aminophenyl)-1-piperazinyl]-carbonyl}-2H-1-benzopyran-6-ol:

The experimental protocol used is the same as that described forintermediate 2.2, with3,4-dihydro-2,5,7,8-tetramethyl-2-{4-[(4-nitrophenyl)-1-piperazinyl]-carbonyl}-2H-1-benzopyran-6-olreplacing the3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-[(4-nitrophenyl)methyl]-benzamide.The product of the reaction is purified on a silica gel column (eluant:dichloromethane/methanol: 9/1). The pure fractions are collected toproduce, after evaporation of the solvent under vacuum, a brown oil witha yield of 66%.

NMR ¹H (100 MHz, CDCl₃, δ): 6.70 (m, 4H, Ph); 4.15-2.97 (m, 8H,piperazine); 2.80-0.90 (m, 18H, Trolox®).

13.3)N-{4-[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)-carbonyl]-1-piperazinyl]phenyl}-2-thiophenecarboximidamidehydrochloride: 13

The experimental protocol used is the same as that described for thecompound 1, with3,4-dihydro-2,5,7,8-tetramethyl-2-{4-[(4-aminophenyl)-1-piperazinyl]-carbonyl}-2H-1-benzopyran-6-olreplacing the3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-(4-amino-phenyl)-benzamide.However, the reaction is slower and requires 15 hours of heating. Thebase obtained after extraction is purified on a silica gel column(eluant: petroleum ether (B.p. 40-70° C.)/ethyl acetate: 3/7). The purefractions are concentrated under vacuum and the evaporation residue issalified in the presence of a molar solution of HCl in anhydrous diethylether. A yellow powder pale is obtained with a yield of 40%. Meltingpoint: 210-211° C.

NMR ¹H (400 MHz, DMSO d6, δ): 11.50 (s, 1H, NH⁺); 9.79 (s, 1H, NH⁺);8.69 (s, 1H, NH⁺); 8.19 (m, 2H, thiophene); 7.38 (m, 1H, thiophene);7.20 (m, 4H, Ph); 4.58 (wide s, 1H, OH); 4.11 (m, 2H, piperazine); 3.61(m, 2H, piperazine); 3.19 (m, 4H, piperazine); 2.62-1.55 (m, 16H,Trolox®). IR: ν_(OH): 3410 cm⁻¹; ν_(C═O) (amide): 1642 cm⁻¹; ν_(C═N)(amidine): 1613 cm⁻¹.

Example 14 N-{4-[4-[(5methoxy-1H-indol-3-yl)methylcarbonyl]-1-piperazinyl]phenyl}-2-thiophenecarboximidamide:14

14.1)1-[(5-methoxy-1H-indol-3-yl)methylcarbonyl]-4-(4-nitrophenyl)piperazine:

In a 100 ml flask, 1.62 g (10 mmoles) of 1.1′-carbonyl-diimidazole isadded to a solution of 2.05 g (10 mmoles) of 5-methoxyindole-3-aceticacid in 10 ml of THF. After one hour of agitation at ambienttemperature, a solution of 1-(4-nitrophenyl)piperazine in 10 ml of DMFis added dropwise. Agitation is continued for 15 hours. The reactionmedium is then concentrated under vacuum and the evaporation residue isprecipitated from 50 ml of an ethyl acetate/water mixture (1/1). Afterfiltration, the solid is rinsed successively with 50 ml of water, 50 mlof ethyl acetate and 50 ml of dichloromethane. After drying undervacuum, a yellow powder is obtained with a yield of 91%. Melting point:239-240° C.

NMR ¹H (100 MHz, DMSO d6, δ): 10.90 (m, 1H, NH); 7.63 (m, 4H, Ph-NO₂);7.40-7.15 (m, 3H, indol); 6.87 (dd, 1H indol, J_(ortho)=8.7 Hz,J_(meta)=2.8 Hz); 3.90 (s, 2H, CH₂—CO); 3.88 (s, 3H, OCH₃); 3.79 (m, 4H,piperazine); 3.50 (m, 4H, piperazine).

14.2) 1-[(5methoxy-1H-indol-3-yl)methylcarbonyl]-4-(4-aminophenyl)-piperazine:

In a 250 ml Parr flask, 1 g (2.53 mmoles) of intermediate 14.1 isdissolved in 30 ml of DMSO in the presence of 10% Pd/C. The mixture isagitated under 20 PSI of hydrogen, at 25° C., for 7 hours. Afterfiltration on celite, the filtrate is concentrated under vacuum. Theevaporation residue is diluted in 50 ml of ethyl acetate and washed with3×50 ml of water. The organic phase is then extracted with 2×25 ml of amolar solution of HCl. After the acid solution is washed with 2×25 ml ofethyl acetate, it is alkalinized using sodium carbonate in powder form.Once the product is re-extracted using 2×50 ml of ethyl acetate, theorganic solution is dried over sodium sulphate, filtered and the solventis evaporated off under vacuum. The residue is purified on a silica gelcolumn (eluant: dichloromethane/methanol: 98/2). The pure fractions arecollected and after evaporation of the solvent under reduced pressure,0.39 g of a pale yellow powder is obtained with a yield of 46%. Meltingpoint: 119-120° C.

NMR ¹H (100 MHz, CDCl₃, δ): 8.32 (s, 1H, indolic NH); 7.27-6.80 (m, 4H,indole); 6.69 (m, 4H, Ph-NH₂); 3.82 (s, 3H, OCH₃); 3.80 (s, 2H, CH₂—CO);3.80 (m, 2H, piperazine); 3.62 (m, 2H, piperazine); 3.48 (s, 2H, NH₂);2.90 (m, 4H, piperazine).

14.3) N-{4-[4-[(5methoxy-1H-indole-3-yl)methylcarbonyl]-1-piperazinyl]phenyl}-2-thiophenecarboximidamide:14

The experimental protocol used is the same as that described for thecompound 1, with 1-[(5methoxy-1H-indole-3-yl)methylcarbonyl]-4-(4-aminophenyl)-piperazinereplacing the3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-(4-aminophenyl)-benzamide. Theexpected product is isolated in the form of the free base with a yieldof 20% (pale yellow powder). Melting point: 221-222° C.

NMR ¹H (400 MHz, DMSO d6, δ): 10.78 (s, 1H, indolic NH); 7.72 (m, 1H,thiophene); 7.59 (m, 1H, thiophene); 7.22 (d, 1H, indole, J=8.7 Hz);

7.19 (m, 1H, thiophene); 7.09 (m, 2H, indole); 6.82 (m, 4H, Ph); 6.72(m, 1H indole); 6.35 (s, 2H, NH₂); 3.80 (s, 2H, CH₂); 3.73 (s, 3H, CH₃);3.62 (m, 4H, piperazine); 2.95 (m, 4H, piperazine). IR: ν_(OH): 3414cm⁻¹; ν_(C═O) (amide): 1628 cm⁻¹; ν_(C═N) (amidine): 1590 cm⁻¹.

Example 15N-[4-[4-[{3-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-1-oxo-2-propenyl}-1-piperazinyl]-phenyl]]-2-thiophenecarboximidamidefumarate: 15

15.1)2,6-bis-(1,1-dimethylethyl)-4-{3-[4-(4-nitrophenyl)-1-piperazinyl]-3-oxo-2-propenyl}-phenol:

The experimental protocol used is the same as that described forintermediate 11.1, with 3,5-di-tert-butyl-4-hydroxycinnamic acidreplacing the syringic acid. An oil is obtained with a yield of 60%.

NMR ¹H (100 MHz, CDCl₃, δ): 7.71 (d, 1H, C═CH, J=15.0 Hz); 7.51 (m, 4H,Ph-NO₂); 7.38 (s, 2H, Ph); 6.69 (d, 1H, HC=C, J=15.0 Hz); 5.50 (s, 1H,OH); 3.88 (m, 4H, piperazine); 3.53 (m, 4H, piperazine); 1.47 (s, 18H,2× tBu).

15.2)2,6-bis-(1,1-dimethylethyl)-4-{3-[4-(4-aminophenyl)-1-piperazinyl]-3-oxo-2-propenyl}-phenol:

In a 50 ml flask equipped with a refrigerant, 0.5 g (1 mmole) ofintermediate 15.1 is dissolved in 5 ml of concentrated hydrochloric acidand 5 ml of absolute ethanol. The mixture is cooled down to 0° C. and1.69 g (7.5 mmoles) of tin chloride (dihydrate) is added in severalportions. After this addition, the reaction medium is heated underreflux for 30 minutes. The solvents are then evaporated off undervacuum, the residue is taken up in 15 ml of water, neutralized with 2Nsoda and diluted with 20 ml of dichloromethane. The precipitate obtainedis filtered on celite and the filtrate is decanted. The organic phase isdried over sodium sulphate, filtered and concentrated under reducedpressure to produce 0.3 g (67%) of a yellow oil.

NMR ¹H (100 MHz, CDCl₃, δ): 7.66 (d, 1H, C═CH, J=15.0 Hz); 7.37 (s, 2H,Ph); 6.75 (m, 4H, Ph-NH₂); 6.30 (d, 1H, HC=C, J=15.0 Hz); 5.46 (s, 1H,OH); 3.80 (m, 4H, piperazine); 3.06 (m, 4H, piperazine); 1.46 (s, 18H,2× tBu).

15.3)N-[4-[4-[{3-[3,5-bis-(1,1-dimethylethyl)-4-hydroxy-phenyl]-1-oxo-2-propenyl}-1-piperazinyl]-phenyl]]-2-thiophenecarboximidamidefumarate: 15

The experimental protocol used is the same as that described forcompound 1, with2,6-bis-(1,1-dimethylethyl)-4-{3-[4-(4-aminophenyl)-1-piperazinyl]-3-oxo-2-propenyl}-phenolreplacing the3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-(4-aminophenyl)-benzamide.

The product of the reaction is salified in the presence of an equimolarquantity of fumaric acid in ethanol under reflux. Compound 15 isobtained in the form of a yellow powder with a yield of 22%. Meltingpoint: 170.5-173° C.

NMR ¹H (400 MHz, DMSO d6, δ): 7.77 (s, 1H, thiophene); 7.67 (d, 1H,thiophene, J=5.0 Hz); 7.48 (d, 1H, C═CH, J=15.0 Hz); 7.39 (s, 2H, Ph);7.34 (wide s, 1H, OH); 7.13 (t, 1H, thiophene, J=4.0 Hz); 7.05 (d, 1H,HC═C, J=15.0 Hz); 6.92 (m, 4H, Ph-N); 6.60 (s, 2H, CH═CH fumarate); 3.78(m, 4H, piperazine); 3.13 (m, 4H, piperazine); 1.41 (s, 18H, 2× tBu).IR: ν_(OH): 3619 cm⁻¹, 3300 cm⁻¹; ν_(C═)(amide): 1640 cm⁻¹; ν_(C═C):1600 cm⁻¹; ν_(C═N) (amidine): 1570 cm⁻¹.

Example 163,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-{3-[[(2-thienyl-(imino)methyl)amino]phenyl]methyl}-benzamidehydrochloride: 16

16.1)3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-[(3-nitrophenyl)methyl]-benzamide:

The experimental protocol used is the same as that described forintermediate 2.1, with 3-nitrobenzylamine hydrochloride replacing the4-nitrobenzylamine hydrochloride. A white powder is obtained with ayield of 63%. Melting point: 210-211° C.

NMR ¹H (100 MHz, DMSO, δ): 9.12 (m, 1H, NH); 8.25 (m, 2H, Ph-NO₂); 7.80(m, 4H, Ph-NO₂ +Ph-OH); 7.60 (wide s, 1H, OH); 4.68 (d, 2H, CH₂, J=6Hz); 1.55 (s, 18H, 2×tBu).

16.2)3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-[(3-aminophenyl)methyl]-benzamide:

In a 250 ml Parr flask, 2.40 g (6.2 mmoles) of3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-[(3-nitrophenyl)methyl]-benzamideis dissolved in 45 ml of an absolute ethanol/THF mixture (1/2) in thepresence of 10% Pd/C. The mixture is agitated under 20 PSI of hydrogen,at 30° C., for three hours. After filtration on celite, the filtrate isconcentrated to dryness and the residue is purified on a silica column(eluant: heptane/ethyl acetate: 60 /40). The pure fractions arecollected and concentrated under reduced pressure to produce 0.94 g(45%) of a white powder. Melting point: 171-172° C.

NMR ¹H (100 MHz, CDCl₃, δ): 7.20 (m, 2H, Ph-NH₂); 6.70 (m, 4H,Ph-NH₂+Ph-OH); 6.34 (m, 1H, NH); 5.55 (s, 1H, OH); 4.56 (d, 2H, CH₂, J=6Hz); 3.70 (wide s, 2H, NH₂); 1.49 (s, 18H, 2×tBu).

16.3)3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-{3-[[(2-thienyl(imino)methyl)-amino]phenyl]methyl}-benzamidehydrochloride: 16

The experimental protocol used is the same as that described forcompound 1, with3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-[(3-aminophenyl)methyl]-benzamidereplacing the3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-(4-aminophenyl)-benzamide. Aftersalification with a molar solution of HCl in an acetone/anhydrousmethanol mixture, a pale yellow powder is obtained with a yield of 50%.Melting point: 226-227° C.

NMR ¹H (400 MHz, DMSO d6, δ): 11.71 (s, 1H, NH⁺); 9.93 (s, 1H, NH⁺);9.10 (s, 1H, CONH); 9.00 (s, 1H, NH⁺); 8.18 (m, 2H, thiophene); 7.70 (s,2H, Ph); 7.42 (m, 6H, thiophene, Ph-NH, OH); 4.50 (d, 2H, CH₂—NHCO,J=5.4 Hz); 1.40 (s, 18H, 2×tBu). IR: ν_(OH): 3420 cm⁻¹; ν_(C═O) (amide):1639 cm⁻¹; ν_(C═N) (amidine): 1578 cm⁻¹.

Example 17N-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N′-{{4-[(2-thienyl(imino)methyl)amino]phenyl}methyl}-ureahydrochloride: 17

17.1) 4-amino-2,6-bis-(1,1-dimethylethyl)-phenol:

In a 250 ml Parr flask, 3.6 g (14 mmoles) of4-nitro-2,6-bis-(1,1-dimethylethyl)-phenol (J. Org. Chem. (1968), 33(1), 223-226) is dissolved in 60 ml of a (2/1) mixture of ethanol anddichloromethane in the presence of a catalytic quantity of 10% Pd/C. Themixture is agitated for 2 hours, at 20° C., under 20 PSI of hydrogen.After filtration on celite, the filtrate is concentrated to drynessunder reduced pressure. The reddish-brown powder obtained is suspendedin heptane (30 ml), filtered and rinsed with the same volume of heptane.The expected product is obtained in the form of an salmon pink powderwith a yield of 50% (1.56 g). Melting point: 123-124° C.

NMR ¹H (100 MHz, CDCl₃, δ): 6.60 (s, 2H, Ph); 4.65 (wide s, 1H, OH);3.15 (wide s, 2H, NH₂); 1.42 (s, 18H, 2× tBu).

17.2) 4-nitrophenylacetic acid chloride:

3.75 ml (7.5 mmoles) of a 2M solution of oxalyl chloride indichloromethane is added at 20° C. to a solution of 0.9 g (5 mmoles) of4-nitrophenylacetic acid in a mixture composed of 10 ml ofdichloromethane and 0.5 ml of DMF. After agitation for 30 minutes, thesolution is concentrated under vacuum. The yellow oil obtained is usedwithout additional purification in the following stage.

17.3) 4-nitrobenzylisocyanate:

The chloride of 4-nitrophenylacetic acid in solution in dry acetone (7.5ml) is slowly added to an aqueous solution of 0.75 g (11.5 mmoles) ofsodium azide, cooled down to 0° C. Agitation of the medium is maintainedfor one hour after the addition is completed, at 0-5° C. The reactionmedium is then diluted with 30 ml of chloroform, decanted and theorganic phase washed with water (20 ml) followed by a saturated solutionof sodium chloride (20 ml). After drying over sodium sulphate, theorganic solution is filtered and partly concentrated (≈20 ml) undervacuum. This solution of the acylazide in chloroform is then heated,under reflux, for one hour. The isocyanate obtained is used directly, insolution, in the following stage.

17.4)N-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N′-[(4-nitrophenyl)methyl]-urea:

1.1 g (5 mmoles) of 4-amino-2,6-bis-(1,1-dimethylethyl)-phenol is addedin one portion to the isocyanate solution (intermediate 17.3)(theoretically 5 mmoles) in 20 ml of chloroform. After agitation for 2hours at 20° C., the precipitate which appears is filtered out andrinsed with chloroform (2×20 ml). A yellow powder is obtained with ayield of 72%. Melting point: 240-241° C.

NMR ¹H (100 MHz, DMSO d6, δ): 8.60 (s, 1H, NH-Ph); 8.01 (m, 4H, Ph-NO₂);7.30 (s, 2H, Ph-OH); 6.77 (m, 1H, NH—CH₂); 6.71 (s, 1H, OH); 4.52 (d,2H, CH₂, J=5.5 Hz); 1.49 (s, 18H, 2× tBu).

17.5)N-[(4-aminophenyl)methyl]-N′-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-urea:

In a 100 ml autoclave, 0.55 g (1.38 mmole) ofN-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N′-[(4-nitrophenyl)methyl]-ureais dissolved in a 2/1 mixture of ethanol and ethyl acetate, in thepresence of 10% Pd/C. After hydrogenation for one and a half hours at20° C., under 20 PSI, the mixture is filtered on celite and the filtrateis concentrated under vacuum. The evaporation residue is diluted in 20ml of diethyl ether and the expected product crystallizes spontaneously.The crystals are filtered out and rinsed with 20 ml of diethyl ether. Awhite powder is obtained with a yield of 60% (0.31 g). Melting point:194-195° C.

NMR ¹H (100 MHz, CDCl₃, δ): 7.08 (s, 2H, Ph-OH); 6.87 (m, 4H, Ph-NH₂);6.15 (s, 1H, NH-Ph); 5.14 (s, 1H, OH); 4.89 (m, 1H, NH—CH₂); 4.41 (d,2H, CH₂, J=5.5 Hz); 3.65 (wide s, 2H, NH₂); 1.40 (s, 18H, 2× tBu).

17.6)N-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N′-{{4-[2-thienyl(imino-methyl)amino]phenyl}methyl}-ureahydrochloride: 17

The experimental protocol used is the same as that described forcompound 1, withN-[(4-aminophenyl)methyl]-N′-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-ureareplacing the3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-(4-aminophenyl)-benzamide. Aftersalification with a molar solution of HCl in anhydrous diethyl ether, awhite powder is obtained with a yield of 45%. Melting point: 236-237° C.

NMR ¹H (400 MHz, DMSO d6, δ): 11.42 (wide s, 1H, NH⁺); 9.77 (wide s, 1H,NH⁺); 8.92 (wide s, 1H, NH⁺); 8.54 (s, 1H, NH-Ph); 8.11 (m, 2H,thiophene); 7.41 (m, 5H, Ph-N, thiophene); 7.19 (s, 2H, Ph); 6.70 (m,1H, NH—CH₂); 6.60 (s, 1H, OH); 4.35 (d, 2H, CH₂, J=5.5 Hz); 1.34 (s,18H, 2× tBu). IR: ν_(OH): 3624 cm⁻¹; ν_(C═O) (urea): 1644 cm⁻¹; ν_(C═N)(amidine): 1569 cm⁻¹.

Example 18N-[5-[{3-(3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl)-1-oxo-2-propenyl}-amino]-2-hydroxyphenyl]-2-thiophenecarboximidamidehydrochloride: 18

18.1)3-[(3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N-(4-hydroxy-3-nitrophenyl)-2-propenamide:

1.78 g (6.4 mmoles) of 3,5-di-tert-butyl-4-hydroxycinnamic acid, 0.99 g(6.4 mmoles) of 4-amino-2-nitrophenol, previously diluted in 10 ml ofDMF, 0.86 g (6.4 mmoles) of hydroxybenzotriazol and 1.32 g (6.4 mmoles)of dicyclohexylcarbodiimide are introduced into a 50 ml flask containing10 ml of THF. The reaction medium is agitated for 15 hours at ambienttemperature, the precipitate which appears is filtered and rinsed withethyl acetate. After concentration of the solution under reducedpressure, the residue is diluted in 20 ml of ethyl acetate and theinsoluble part is filtered again. The filtrate is washed with 20 ml of asaturated solution of sodium carbonate followed by 20 ml of water and 20ml of a saturated solution of sodium chloride. After drying over sodiumsulphate, the organic solution is filtered and concentrated to drynessunder reduced pressure. The residue is purified on a silica column(eluant: heptane/ethyl acetate: 8/2). The pure fractions are collectedand concentrated under vacuum to produce 1.95 g (47%) of the expectedcompound in the form of a yellow-orange powder. Melting point: 231-232°C.

NMR ¹H (100 MHz, CDCl₃, δ): 10.45 (s, 1H, NH); 8.45 (d, 1H, Ph-NO₂,J=1.7 Hz); 7.98 (dd, 1H, Ph-NO₂, J=1.7 Hz and J=6.8 Hz); 7.78 (d, 1H,—CH═CH—, J=10.5 Hz); 7.75 (s, 1H, OH); 7.40 (s, 2H, Ph-OH); 7.20 (d, 1H,Ph-NO₂); 6.48 (d, 1H, —H═CH—); 5.51 (s, 1H, OH); 1.50 (s, 18H, 2×tBu).

18.2)3-[(3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N-(4-hydroxy-3-aminophenyl)-2-propenamide:

In a 100 ml flask equipped with a refrigerant, 0.9 g (2.18 mmoles) of3-[(3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N-(4-hydroxy-3-nitrophenyl)-2-propenamideis dissolved in 20 ml of ethyl acetate, 2.46 g (10.9 mmoles) of tinchloride (dihydrate) is added and the mixture is heated at 70° C. forthree hours. After returning to ambient temperature, the reaction mediumis poured onto an agitated solution of sodium bicarbonate (0.1 M), aprecipitate forms, which is eliminated by filtration on celite. Thefiltrate is decanted and the aqueous phase is extracted with 20 ml ofethyl acetate. The organic phases are collected together and washed with20 ml of water followed by 20 ml of a saturated solution of sodiumchloride. After drying over sodium sulphate and filtration, the organicsolution is concentrated to dryness, under partial vacuum. Theevaporation residue is suspended in a heptane/ethyl acetate mixture(1/1) and filtered to produce a yellowish powder with a yield of 53%.The product is used as it is in the following stage.

18.3)N-[5-[{3-(3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl)-1-oxo-2-propenyl}amino]-2-hydroxyphenyl]-2-thiophenecarboximidamidehydrochloride: 18

The experimental protocol used is the same as that described forcompound 1, with3-[(3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N-(4-hydroxy-3-aminophenyl)-2-propenamidereplacing the3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-(4-aminophenyl)-benzamide. Thefree base is purified on a silica column (eluant: heptane/ethyl acetate:35/65). The pure fractions are collected and concentrated under reducedpressure. The evaporation residue is diluted in 10 ml of acetone andsalified with a molar solution of HCl in anhydrous ether, as describedpreviously. 0.35 g (62%) of a yellow powder is obtained. Melting point:199-200° C.

NMR ¹H (400 MHz, DMSO, δ): 11.11 (s, 1H, NH⁺); 10.29 (s, 1H, NH⁺); 10.17(s, 1H, NH⁺); 9.71 (s, 1H, CONH); 8.61 (wide s, 1H, OH); 8.14 (m, 2H,thiophene); 7.79 (s, 1H, Ph-N); 7.53 (m, 1H, Ph-N); 7.48 (d, 1H,—CH═CH—, J=14.7 Hz); 7.37 (m, 4H, Ph-tBu+OH+Ph-N); 7.05 (m, 1H,thiophene); 6.68 (d, 1H, —CH═CH—); 1.41 (s, 18H, 2×tBu). IR: ν_(OH):3624 cm⁻¹, 3415 cm⁻¹; ν_(C═O) (amide): 1656 cm⁻¹; ν_(C═C): 1616 cm⁻¹;ν_(C═N) (amidine): 1587 cm⁻¹.

Example 19N-[3-[{3-(3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl)-1-oxo-2-propenyl}-amino]-4-hydroxyphenyl]-2-thiophenecarboximidamidehydrochloride: 19

19.1)3-[(3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N-(2-hydroxy-5-nitrophenyl)-2-propenamide:

The experimental protocol used is the same as that described forintermediate 18.1, with 2-amino-4-nitrophenol replacing the4-amino-2-nitrophenol. A light yellow powder is obtained with a yield of25%. Melting point: 256-257° C.

NMR ¹H (400 MHz, DMSO, δ): 11.79 (wide s, 1H, OH); 9.59 (s, 1H, NH);9.21 (wide s, 1H, Ph-NO₂); 7.90 (badly resolved dd, 1H, Ph-NO₂, J=8.1Hz); 7.52 (d, 1H, —CH═CH—, J=15.5 Hz); 7.47 (s, 1H, OH); 7.42 (s, 2H,Ph-OH); 7.15 (d, 1H, —CH═CH—); 7.04 (d, 1H, Ph-NO₂); 1.42 (s, 18H,2×tBu).

19.2)3-[(3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N-(2-hydroxy-5-aminophenyl)-2-propenamide:

The experimental protocol used is the same as that described forintermediate 18.2, with3-[(3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N-(2-hydroxy-5-nitrophenyl)-2-propenamidereplacing the3-[(3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N-(4-hydroxy-3-nitrophenyl)-2-propenamide.A yellow powder is obtained with a yield of 74%. The product is usedwithout additional purification in the following stage.

19.3)N-[5-[{3-(3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl)-1-oxo-2-propenyl}-amino]-2-hydroxyphenyl]-2-thiophenecarboximidamidehydrochloride: 19

The experimental protocol used is the same as that described forcompound 1, with3-[(3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N-(2-hydroxy-5-aminophenyl)-2-propenamidereplacing the3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-(4-aminophenyl)-benzamide. Aftersalification with a molar solution of HCl in anhydrous diethyl ether, ayellow powder is obtained with a yield of 54%. Melting point: 256-257°C.

NMR ¹H (400 MHz, DMSO d6, δ): 11.32 (s, 1H, NH⁺); 10.67 (s, 1H, NH⁺);9.69 (s, 1H, NH⁺); 9.55 (s, 1H, CONH); 8.70 (wide s, 1H, OH); 8.19 (m,2H, thiophene); 7.48 (d, 1H, —CH═CH—, J=15.5 Hz); 7.40 (s, 2H, Ph-tBu);7.37 (m, 2H, Ph-N); 7.34 (s, 1H, OH); 7.13 (d, 1H, —CH═CH—); 7.10 (m,1H, Ph-N); 6.99 (m, 1H, thiophene); 1.41 (s, 18H, 2×tBu). IR: ν_(OH):3623 cm⁻¹, 3410 cm⁻¹; ν_(C═O) (amide): 1652 cm⁻¹; ν_(C═C): 1616 cm⁻¹;ν_(C═N) (amidine): 1587 cm⁻¹.

Example 20N-{4-[4-[3,4,5-trihydroxybenzoyl]-1-piperazinyl]phenyl}-2-thiophenecarboximidamidehydrochloride: 20

20.1) 5-{[4-(4-nitrophenyl)-1-piperazinyl]carbonyl}-benzene-1,2,3-triol:

The experimental protocol is the same as that described for intermediate8.1, with 1-(4-nitrophenyl)piperazine replacing the4-nitrophenetylamine. A yellow powder still containing traces ofimpurities is obtained with a yield of 43%.

NMR ¹H (100 MHz, DMSO, δ): 9.17 (wide s, 2H, 2× —OH); 8.55 (wide s, 1H,—OH); 7.57 (m, 4H, Ph-NO₂); 6.40 (s, 2H, Ph-OH); 3.59 (badly resolved m,8H, piperazine).

20.2) 5-{[4-(4-aminophenyl)-1-piperazinyl]carbonyl)-benzene-1,2,3-triol:

The experimental protocol used is the same as that described forintermediate 2.2, with5-{[4-(4-nitrophenyl)-1-piperazinyl]carbonyl}-benzene-1,2,3-triolreplacing the3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-[(4-nitrophenyl)methyl]-benzamide.A beige powder is obtained with a yield of 61%. This is used directly inthe following stage without additional purification.

NMR ¹H (100 MHz, DMSO, δ): 9.12 (wide s, 2H, 2× —OH); 8.55 (wide s, 1H,—OH); 6.61 (m, 4H, Ph-NH₂); 6.34 (s, 2H, Ph-OH); 3.59 (m, 4H,piperazine); 2.89 (m, 4H, piperazine).

20.3)N-{4-[4-[3,4,5-trihydroxybenzoyl]-1-piperazinyl]phenyl}-2-thiophenecarboximidamidehydrochloride: 20

The experimental protocol used is the same as that described forcompound 1, with5-{[4-(4-aminophenyl)-1-piperazinyl]carbonyl}-benzene-1,2,3-triolreplacing the3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-(4-aminophenyl)-benzamide. Aftertreatment with a molar solution of HCl in anhydrous diethyl ether, abrown powder is obtained with a yield of 25%. Melting point: 198-205° C.

NMR ¹H (400 MHz, DMSO d6, δ): 11.38 (s, 1H, NH⁺); 9.75 (s, 1H, NH⁺);9.00 (wide s, 1H, OH); 8.75 (s, 1H, NH⁺); 8.15 (m, 2H, thiophene); 7.39(m, 1H, thiophene); 7.22 (m, 4H, Ph-N); 6.40 (s, 2H, Ph); 5.11 (wide s,2H, 2×OH); 3.65 (m, 4H, piperazine); 3.29 (m, 4H, piperazine). IR:ν_(OH): 3399 cm⁻¹; ν_(C═O) (amide): 1696 cm⁻¹; ν_(C═N) (amidine): 1588cm⁻¹.

Example 21N-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N′-{{4-[(2-thienyl(imino)methyl)amino]phenyl}carbonylamino}-ureahydrochloride: 21

21.1)N-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N′-[(4-nitrophenyl)-carbonylamino]-urea:

0.22 g (0.73 mmole) of triphosgene at 20° C. is dissolved in a 50 mlthree-necked flask equipped with an addition funnel, under an argonatmosphere. Over one hour, a solution of 0.44 g (2 mmoles) of4-amino-2,6-bis-(1,1-dimethylethyl)-phenol (intermediate 17.1) and 0.38ml (2.2 mmoles) of diisopropylethylamine in 7 ml of anhydrousdichloromethane is added dropwise to this mixture. Five minutes afterthe end of this addition, a solution of 0.36 g (2 mmoles) of4-nitrobenzoyl-hydrazide and 0.38 ml (2.2 mmoles) ofdiisopropylethylamine in 4 ml of anhydrous DMF is added in a singleportion. After agitation for four hours at 20° C., the reaction mediumis concentrated to dryness under reduced pressure. The evaporationresidue is diluted in 40 ml of ethyl acetate and the organic solution iswashed successively with 3 times 20 ml of water and 20 ml of a saturatedsolution of sodium chloride. After drying over sodium sulphate, theorganic solution is filtered and the filtrate concentrated to drynessunder reduced pressure. The residue obtained is suspended in heptane,agitated and filtered to produce a yellow powder with a yield of 86%.Melting point: 163-164° C.

NMR ¹H (100 MHz, DMSO d6, δ): 10.65 (wide s, 1H, NH amide); 8.72 (s, 1H,NH-Ph); 8.38 (m, 4H, Ph-NO₂); 8.20 (s, 1H, CO—NH—NH); 7.36 (s, 2H,Ph-OH); 6.78 (s, 1H, OH); 1.50 (s, 18H, 2×tBu).

21.2)N-[(4-aminophenyl)carbonylamino]-N′-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-urea:

In a 250 ml Parr flask, 0.72 g (1.68 mmoles) ofN-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N′-[(4-nitrophenyl)carbonylamino]-ureais dissolved in 30 ml of absolute ethanol in the presence of 10% Pd/C.The mixture is agitated under 20 PSI of hydrogen, at 30° C., for twohours. After filtration on celite, the filtrate is concentrated undervacuum. The evaporation residue is suspended in diethyl ether (20 ml),agitated and filtered to produce a pale yellow powder with a yield of75%. Melting point: 245-246° C.

NMR ¹H (100 MHz, DMSO d6, δ): 9.84 (wide s, 1H, NH amide); 8.56 (s, 1H,NH-Ph); 7.85 (m, 2H, Ph-NH₂); 7.74 (s, 1H, CO—NH—NH); 7.38 (s, 2H,Ph-OH); 6.78 (s, 1H, OH); 6.60 (m, 2H, Ph-NH₂); 5.80 (wide s, 2H, NH₂);1.50 (s, 18H, 2×tBu).

21.3)N-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N′-{{4-[(2-thienyl(imino)methyl)amino]phenyl}carbonylamino}-ureahydrochloride: 21

The experimental protocol used is the same as that described forcompound 1, with N-[(4-aminophenyl)carbonylamino]-N′-[3,5-bis-(1,1-dimethylethyl)-4-hydroxy phenyl]-ureareplacing the3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-(4-aminophenyl)-benzamide. Thefree base is purified on a silica column (eluant: heptane/ethyl acetate:1/1). The pure fractions are collected and concentrated under reducedpressure. The evaporation residue is diluted in 15 ml of acetone andsalified with a molar solution of HCl in anhydrous ether, as describedpreviously. 0.40 g (58%) of a yellow powder is obtained. Melting point:254-255° C.

NMR ¹H (400 MHz, DMSO, δ): 11.68 (wide s, 1H, NH⁺); 10.32 (s, 1H, NHamide); 9.94 (wide s, 1H, NH⁺); 9.13 (wide s, 1H, NH⁺); 8.68 (s, 1H,NH—CO); 8.18 (m, 2H, thiophene); 8.07 (m, 3H, CO—NH—NH+Ph-NH); 7.58 (m,2H, Ph-NH); 7.39 (m, 1H, thiophene); 7.22 (s, 2H, Ph-OH); 6.60 (s, 1H,OH); 1.36 (s, 18H, 2×tBu). IR: ν_(OH): 3627 cm⁻¹; ν_(C═O) (amide),ν_(C═O) (urea): 1654 cm⁻¹, 1602 cm⁻¹; ν_(C═N) (amidine): 1559 cm⁻¹.

Example 22N-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N′-{{4-[(2-thienyl(imino)methyl)amino]phenyl}methyl}-thioureahydrochloride: 22

22.1)N-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N′-[(4-nitrophenyl)methyl]-thiourea:

Compound 22.1 is obtained by the action of Lawesson's reagent onintermediate 17.4 according to an experimental protocol described in theliterature (J. Med. Chem. (1995), 38 (18), 3558-3565). A light yellowpowder is obtained with a yield of 80%. Melting point: 218-220° C.

NMR ¹H (100 MHz, CDCl₃, δ): 7.85 (m, 4H, Ph-NO₂); 7.70 (s, 1H, NH-Ph);7.05 (s, 2H, Ph-OH); 6.21 (m, 1H, NH—CH₂); 5.40 (s, 1H, OH); 5.00 (d,2H, CH₂, J=6.5 Hz); 1.41 (s, 18H, 2×tBu).

2.2)N-[(4-aminophenyl)methyl]-N′-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-thiourea:

The experimental protocol used is the same as that described forintermediate 18.2, with intermediate 22.1 replacing the3-[(3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N-(4-hydroxy-3-nitrophenyl)-2-propenamide.A beige powder is obtained with a yield of 70%. Melting point: 167-169°C.

NMR ¹H (100 MHz, CDCl₃, δ): 7.48 (wide s, 1H, NH-Ph); 6.95 (s, 2H,Ph-OH); 6.81 (m, 4H, Ph-NH₂); 5.98 (m, 1H, NH—CH₂); 5.28 (s, 1H, OH);4.69 (d, 2H, CH₂, J=5.5 Hz); 3.62 (wide s, 2H, NH₂); 1.40 (s, 18H,2×tBu).

22.3)N-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N′-{4-[(2-thienyl(imino)methyl)amino]phenyl}methyl}-thioureahydrochloride: 22

The experimental protocol used is the same as that described forintermediate 17.6, with intermediate 22.2 replacing theN-[(4-aminophenyl)methyl]-N′-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-urea.A pale yellow powder is obtained with a yield of 15%. Melting point:203-205° C.

NMR ¹H (400 MHz, DMSO d6, δ): 11.52 (wide s, 1H, NH⁺); 9.86 (wide s, 1H,NH⁺); 8.98 (wide s, 1H, NH⁺); 8.39 (s, 1H, NH-Ph); 8.16 (m, 2H,thiophene); 7.46 (m, 6H, Ph-N, thiophene, NH—CH₂); 7.18 (s, 2H, Ph);6.92 (s, 1H, OH); 4.80 (wide s, 2H, CH₂); 1.35 (s, 18H, 2×tBu). IR:ν_(OH): 3630 cm⁻¹; ν_(C═O) (urea): 1649 cm⁻¹; ν_(C═N) (amidine): 1600cm⁻¹.

Example 23N-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N′-{2-{4-[(2-thienyl(imino)methyl)amino]phenylethyl}-ureahydrochloride: 23

23.1)N-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N′-[2-(4-nitrophenyl)ethyl]-urea:

The experimental protocol used is the same as that described forintermediate 21.1, with 4-nitrophenetylamine replacing the4-nitrobenzoyl-hydrazide. A beige powder is obtained with a yield of80%. Melting point: 185-187° C.

NMR ¹H (100 MHz, CDCl₃, δ): 7.75 (m, 4H, Ph-NO₂); 7.00 (s, 2H, Ph-OH);6.05 (s, 1H, OH); 5.18 (s, 1H, NH); 4.68 (m, 1H, NH—CH₂); 3.50 (m, 2H,NH-CH₂); 2.92 (m, 2H, CH₂); 1.40 (s, 18H, 2×tBu).

23.2)N-[2-(4-aminophenyl)ethyl]-N′-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-urea:

The experimental protocol used is the same as that described forintermediate 21.2, with intermediate 23.1 replacing theN-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N′-[(4-nitrophenyl)-carbonylamino]-urea.A white powder is obtained with a yield of 56%. Melting point: 192-194°C.

NMR ¹H (100 MHz, DMSO d6, δ): 8.25 (wide s, 1H, Ph-NH—CO); 7.22 (s, 2H,Ph-OH); 6.79 (m, 4H, Ph-NH₂); 6.65 (s, 1H, OH); 5.92 (m, 1H, NH—CH₂);4.98 (wide s, 2H, —NH₂); 3.31 (m, 2H, NH—CH₂); 2.65 (m, 2H, CH₂) 1.48(s, 18H, 2×tBu).

23.3)N-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N′-{2-{4-[(2-thienyl(imino)methyl)amino]phenyl}ethyl}-ureahydrochloride: 23

The experimental protocol used is the same as that described forcompound 1, with intermediate 23.2 replacing the3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-(4-aminophenyl)-benzamide. Thefree base is purified on a silica column (eluant: heptane/ethyl acetate:1/1). The pure fractions are collected and concentrated under reducedpressure. The evaporation residue is diluted in 15 ml of acetone andsalified with a molar solution of HCl in anhydrous ether, as describedpreviously. Finally, 0.25 g (24%) of a pale yellow powder is obtained.Melting point: 207-210° C.

NMR ¹H (400 MHz, DMSO d6, δ): 11.48 (wide s, 1H, NH⁺); 9.83 (wide s, 1H,NH⁺); 8.95 (wide s, 1H, NH⁺); 8.50 (s, 1H, NH—CO); 8.18 (m, 2H,thiophene); 7.38 (m, 5H, Ph-NH+thiophene); 7.18 (s, 2H, Ph-OH); 6.55 (s,1H, OH); 6.21 (m, 1H, CO—NH—CH₂); 3.35 (m, 2H, NH—CH₂); 2.78 (m, 2H,CH₂); 1.36 (s, 18H, 2×tBu). IR: ν_(OH): 3631 cm⁻¹; ν_(C═O) (urea): 1654cm⁻¹, 1600 cm⁻¹; ν_(C═N) (amidine): 1560 cm⁻¹.

Example 24N-(4-{4-[(3,4-dihydro-6-methoxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)carbonyl]-1-piperazinyl}phenyl)-2-thiophenecarboximidamidehydrochloride: 24

24.1)1-{[3,4-dihydro-6-methoxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl]carbonyl}-4-(4-nitrophenyl)piperazine:

The experimental protocol is identical to that described forintermediate 13.1, with(±)-3,4-dihydro-6-methoxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-carboxyliqueacid (prepared according to CHIMIA (1991), 45 (4), 121-3) replacing the(±)-Trolox®. A yellow powder is obtained.

NMR ¹H (100 MHz, CDCl₃, δ): 7.45 (m, 4H, Ph); 3.60 (s, 3H, CH₃O);®3.40(m, 4H, piperazine); 3.00 (m, 4H, piperazine); 2.50-1.60 (m, 16H,Trolox®).

24.2)1-([3,4-dihydro-6-methoxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl]carbonyl}-4-(4-aminophenyl)piperazine:

The experimental protocol is identical to that described forintermediate 13.2, with intermediate 24.1 replacing the3,4-dihydro-2,5,7,8-tetramethyl-2-{4-[(4-nitrophenyl)-1-piperazinyl]-carbonyl}-2H-1-benzopyran-6-ol.An oil is obtained which is used directly in the following stage.

NMR 1H (100 MHz, CDCl₃, δ): 6.70 (m, 4H, Ph); 3.90 (wide d, 4H,piperazine); 3.60 (s, 3H, CH₃O); 3.45 (wide s, 2H, NH₂); 2.90 (m, 4H,piperazine); 2.60-1.60 (m, 18H, Trolox®).

24.3)N-(4-{4-[(3,4-dihydro-6-methoxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)carbonyl]-1-piperazinyl}phenyl)-2-thiophenecarboximidamidehydrochloride: 24

The experimental protocol is the same as that described for compound 13,with intermediate 24.2 replacing the3,4-dihydro-2,5,7,8-tetramethyl-2-{4-[(4-aminophenyl)-1-piperazinyl]-carbonyl}-2H-1-benzopyran-6-ol.A pale yellow powder is obtained. Melting point: 190-195° C.

NMR ¹H (400 MHz, DMSO, δ): 11.35 (wide s, 1H, NH⁺); 9.70 (wide s, 1H,NH⁺); 8.70 (wide s, 1H, NH⁺); 8.15 (wide s, 2H, thiophene); 7.35 (wides, 1H, thiophene); 7.17 (m, 4H, Ph); 3.90 (wide d, 4H, piperazine); 3.50(s, 3H, CH₃O); 3.15 (m, 4H, piperazine); 2.55-1.55 (m, 16H, Trolox®).IR: ν_(C═O) (amide): 1642 cm⁻¹; ν_(C═N) (amidine): 1618 cm⁻¹.

Example 25N-[4-{4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)carbonyl]-1H-1,4-diazepin-1-yl}phenyl]-2-thiophenecarboximidamidehydrochloride: 25

25.1) hexahydro-4-(4-nitrophenyl)-1H-1,4-diazepine:

3.37 g (24.4 mmoles) of potassium carbonate and 1.89 g (13.4 mmoles) of4-nitrofluorobenzene are added to a solution of 2.44 g (12.2 mmoles) of(1,1-dimethyl) ethyl hexahydro-1H-1,4-diazepine-1-carboxylate in 50 mlof DMF. The reaction medium is heated at 100° C. for 16 hours. Aftercooling down, 25 ml of ethyl acetate and 50 ml of water are added. Theorganic solution is decanted and the aqueous phase extracted with 3times 50 ml of ethyl acetate. The organic phases are collected togetherand washed with 50 ml of brine, dried over sodium sulphate, filtered andconcentrated under vacuum. 3.7 g of a bright yellow solid is obtainedwith a yield of 95%. This solid is then dissolved in 100 ml of a mixtureof solvents (dichloromethane/ethyl acetate 1:1) to which 20 ml of a 6Naqueous solution of hydrochloric acid is added dropwise at 0° C. Aftervigorous agitation at 20° C. for 1 hour, the reaction medium isdecanted. The aqueous phase is basified to pH=11 with 4N soda andextracted with 3 times 50 ml of dichloromethane. The organic phases arecollected, washed with 50 ml of water followed by 50 ml of brine, driedover sodium sulphate and finally filtered and concentrated under vacuum.1.78 g of a bright yellow powder is obtained with a yield of 66%. Theproduct is used directly in the following stage without additionalpurification.

NMR ¹H (100 MHz, CDCl₃, δ): 8.10 (m, 2H, Ph); 6.65 (m, 2H, Ph); 3.70 (q,4H, CH₂N, J=5.2 Hz); 3.10 (t, 2H, CH₂N); 2.85 (t, 2H, CH₂N); 1.95 (q,2H, C—CH₂—C); 1.65 (wide s, 1H NH).

25.2)1-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)carbonyl]hexahydro-4-(4-nitrophenyl)-1H-1,4-diazepine:

In a 50 ml flask, 0.71 g (4.4 mmoles) of 1,1′-carbonyldiimidazole isadded to a solution of 1.07 g (4.3 mmoles) of (±)-Trolox® in 8 ml ofanhydrous THF. After agitation for one hour at 20° C., a solution of0.95 g (4.3 mmoles) of intermediate 25.1 in 4 ml of DMF is addeddropwise. The reaction medium is agitated for 16 hours at 20° C. Afterevaporation of the solvents under vacuum, the residue is taken up in 30ml of a mixture of solvents (dichloromethane/water 1:2). Afterdecanting, the organic phase is washed with 2 times 20 ml of water,dried over sodium sulphate and concentrated under vacuum. A pale yellowpowder is obtained with a gross yield of 97%. The product is useddirectly in the following stage without additional purification.

NMR ¹H (100 MHz, CDCl₃, δ): 8.10 (m, 2H, Ph); 6.60 (m, 2H, Ph); 4.40(wide s, 1H, OH); 3.50 (m, 8H, CH₂N); 2.50-1.50 (m, 18H, Trolox®+CH₂).

25.3)1-(4-aminophenyl)-4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)carbonyl]hexahydro-1H-1,4-diazepine:

The experimental protocol used is the same as that described forintermediate 13.2, with intermediate 25.2 replacing the3,4-dihydro-2,5,7,8-tetramethyl-2-{4-[(4-nitrophenyl)-1-piperazinyl]-carbonyl}-2H-1-benzopyran-6-ol.The product of the reaction is purified on a silica gel column (eluant:ethyl acetate/petroleum ether 3:2). An oil is obtained with a yield of57%.

25.4)N-[4-{4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)carbonyl]-1H-1,4-diazepin-1-ylphenyl]-2-thiophenecarboximidamidehydrochloride:

A mixture of 0.52 g (1.22 mmole) of intermediate 25.3 and 0.35 g (1.22mmole) of S-methyl-2-thiophene thiocarboximide hydriodide in 4 ml ofisopropanol is heated at 50° C. for 40 hours. The reaction medium isthen filtered and the solid obtained is taken up in 4 ml of a saturatedaqueous solution of sodium carbonate and 4 ml of ethyl acetate. Themixture is heated at 50° C. for 30 minutes, then decanted. The organicphase is washed twice with 10 ml of water followed by 10 ml of brine.The organic phases are collected, dried over sodium sulphate, filteredand concentrated under reduced pressure. The solid obtained is purifiedon a silica gel column (eluant: ethyl acetate/petroleum ether 5:1). 0.5g of product is obtained with a yield of 77%. 0.15 g (0.29 mmole) ofthis product is then dissolved in 2 ml of acetone. 0.84 ml (0.84 mmole)of a 1N hydrochloric acid solution in anhydrous ethyl ether is addeddropwise. The whole is agitated at ambient temperature for 30 minutes. Ayellow precipitate forms which is filtered. The precipitate istriturated and washed successively with 3 times 5 ml of ethyl ether and5 ml of acetone. The dark yellow powder is dried under vacuum at 70° C.for 48 hours. The yield obtained is 80%. Melting point: 180-185° C.

NMR ¹H (400 MHz, DMSO, δ): 11.15 (wide s, 1H, NH⁺); 9.60 (wide s, 1H,NH⁺); 8.55 (wide s, 1H, NH⁺); 8.10 (wide s, 2H, thiophene); 7.35 (wides, 1H, thiophene); 7.02 (m, 4H, Ph); 4.80 (wide s, 1H, OH); 3.70 (m, 8H,CH₂N); 2.50-1.40 (m, 18H, Trolox®+CH₂). IR: ν_(OH): 3412 cm⁻¹; ν_(C═O)(amide): 1613 cm⁻¹; ν_(C═N) (amidine): 1613 cm⁻¹.

Example 26(R)-N-{4-[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)-carbonyl]-1-piperazinyl]phenyl}-2-thiophenecarboximidamidehydrochloride: 26

26.1)(R)-3,4-dihydro-2,5,7,8-tetramethyl-2-{4-[(4-nitrophenyl)-1-piperazinyl]-carbonyl}-2H-1-benzopyran-6-ol:

The experimental protocol used is the same as that described forcompound 13. 1, with (R)-Trolox® replacing the (±)Trolox®. A brightyellow powder is obtained with a yield of 98%. Melting point: 102-105°C.

26.2)(R)-3,4-dihydro-2,5,7,8-tetramethyl-2-{4-[(4-aminophenyl)-1-piperazinyl-carbonyl}-2H-1-benzopyran-6-ol:

The experimental protocol used is the same as that described forintermediate 2.2, with intermediate 26.1 replacing the3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-[(4-nitrophenyl)methyl]-benzamide.A pink powder is obtained with a yield of 75%. The product is used as itis in the following stage. Melting point: 103-105° C.

26.3)(R)-N-{4-[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)-carbonyl]-1-piperazinyl]phenyl}-2-thiophenecarboximidamidehydrochloride: 26

The experimental protocol used is the same as that described forcompound 13, with intermediate 26.2 replacing the3,4-dihydro-2,5,7,8-tetramethyl-2-{4-[(4-aminophenyl)-1-piperazinyl)-carbonyl}-2H-1-benzopyran-6-ol.The product is obtained in the form of a pale yellow powder whichhydrates in air. Melting point: 195-197° C.

The NMR and IR analyses are identical to compound 13.[α]_(D)²⁰ = −43.5^(∘)  (c = 0.11;  DMSO)

Example 27(S)-N-{4-[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)-carbonyl]-1-piperazinyl]phenyl}-2-thiophenecarboximidamidedihydrochloride: 27

27.1)(S)-3,4-dihydro-2,5,7,8-tetramethyl-2-(4-[(4-nitrophenyl)-1-piperazinyl]-carbonyl}-2H-1-benzopyran-6-ol:

The experimental protocol used is the same as that described forcompound 13.1, with (S)-Trolox® replacing the (±)Trolox®. A yellowpowder is obtained with a yield of 73%. Melting point: 110-111° C.

27.2)(S)-3,4-dihydro-2,5,7,8-tetramethyl-2-{4-[(4-aminophenyl)-1-piperazinyl]-carbonyl}-2H-1-benzopyran-6-ol:

The experimental protocol used is the same as that described forintermediate 2.2, with intermediate 27.1 replacing the3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-[(4-nitrophenyl)methyl]-benzamide.After purification on a silica gel column (heptane/ethyl acetate: 2/8),collection and evaporation under vacuum of the pure fractions, a beigepowder is obtained with a yield of 54%. Melting point: 109-111° C.

27.3)(S)-N-{4-[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)-carbonyl]-1-piperazinyl]phenyl}-2-thiophenecarboximidamidedihydrochloride: 27

The experimental protocol used is the same as that described forcompound 13, with intermediate 27.2 replacing the3,4-dihydro-2,5,7,8-tetramethyl-2-{4-[(4-aminophenyl)-1-piperazinyl]-carbonyl}-2H-1-benzopyran-6-ol.The product is obtained in the form of a pale yellow powder whichhydrates in air. Melting point: 210.6-211.8° C.

The NMR and IR analyses are identical to compound 13.[α]_(D)²⁰ = +76.2^(∘)  (c = 0.17;  DMSO)

Alternatively, compound 27 can be prepared according to the followingprotocol:

27.4) methyl 2-thiophene carboximidate:

10.91 g (0.1 mole) of 2-thiophene carbonitrile, 100 ml of anhydrousethyl ether and 4.5 ml (0.11 mole) of methanol are introduced into a 250ml erlen meyer flask purged with argon. The solution is cooled down to0° C. using an ice bath and saturated with a stream of anhydrous gaseousHCl for 45 minutes. The reaction medium is agitated for an additionalhour at 0° C. and overnight at 20° C. The precipitate formed is filteredout, washed with ethyl ether and dried. The hydrochloride obtained ispartitioned into a mixture of 100 ml of water and 150 ml of ethyl ether.The medium is neutralized by adding 8.4 g (0.1 mole) of dry NaHCO₃.After decanting and separation, the organic phase is washed successivelywith 2×30 ml of water and 30 ml of brine. After drying over magnesiumsulphate, the organic solution is filtered and concentrated undervacuum. A colourless oil is obtained with a yield of 66%.

NMR ¹H (400 MHz, CDCl₃, δ): 7.58 (wide s, 1H, ═N—H); 7.42 (m, 1H,thiophene); 7.37 (m, 1H, thiophene); 7.01 (m, 1H, thiophene); 3.86 (s,3H, OCH₃). IR: ν_(C═N) (carboximidate): 1630 cm⁻¹.

27.5)(S)-N-{4-[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)-carbonyl]-1-piperazinyl]phenyl}-2-thiophenecarboximidamidedihydrochloride: 27

In a 150 ml erlen meyer flask, under a stream of argon, 8.2 g (20mmoles) of(S)-3,4-dihydro-2,5,7,8-tetramethyl-2-{4-[(4-aminophenyl)-1-piperazinyl]-carbonyl}-2H-1-benzopyran-6-ol(obtained as intermediate 13.2 but from (S)-Trolox®), is dissolved in 60ml of methanol and 4.2 g (30 mmoles) of methyl 2-thiophene carboximidateis added. The reaction medium is heated for 18 hours under reflux. Themethanol is evaporated under vacuum and the oily brown residue ispurified on a silica gel column (eluant: dichloromethane/ethanol: 95/5).The pure fractions are collected and concentrated under vacuum toproduce a brown oil with a yield of 68%. This oil is taken up in 22 mlof an ethanolic solution of HCl (1.3N) and diluted with 180 ml ofanhydrous acetone. The reaction medium is agitated for 1 hour at 0° C.The precipitate formed is filtered and washed successively with acetoneand ethyl ether. After drying, the dihydrochloride is obtained in theform of a pale yellow powder with a yield of 53%.

Example 283,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-{2-[3-[(2-thienyl(imino)methyl)amino]phenyl]ethyl}-benzamidehydrochloride: 28

28.1)3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-[2-(3-nitrophenyl)ethyl]-benzamide:

The experimental protocol used is the same as that described forintermediate 5. 1, with 3-nitrophenetylamine (J. Med. Chem. (1968), 11(1), 21-26) replacing the 4-nitrophenetylamine. A white powder isobtained with a yield of 50%. Melting point: 195-197° C.

NMR ¹H (100 MHz, CDCl₃, δ): 7.86 (m, 4H, Ph-NO₂); 7.50 (s, 2H, Ph); 6.10(m, 1H, NHCO); 5.54 (s, 1H, OH); 3.75 (m, 2H, CH₂—NHCO); 3.08 (m, 2H,CH₂-Ph-NO₂); 1.42 (s, 18H, 2×tBu).

28.2)3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-[2-(3-aminophenyl)ethyl]-benzamide:

The experimental protocol used is the same as that described forintermediate 5.2, with intermediate 28.1 replacing the3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-[2-(4-nitrophenyl)ethyl]-benzamide.A white powder is obtained (yield of 40%) which is sufficiently pure tobe used directly in the following stage.

28.3)3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-{2-[3-[(2-thienyl-(imino)methyl)-amino]phenyl]ethyl}-benzamidehydrochloride: 28

The experimental protocol used is the same as that described forintermediate 1.3, with intermediate 28.2 replacing the3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-(4-aminophenyl)-benzamide. Apale yellow powder is obtained with a yield of 35%. Melting point:205-207° C.

NMR ¹H (400 MHz, DMSO d6, δ): 11.59 (wide s, 1H, NH⁺); 9.89 (s, 1H,NH⁺); 8.95 (s, 1H, NH⁺); 8.46 (s, 1H, CONH); 8.17 (m, 2H, thiophene);7.54 (s, 2H, Ph-OH); 7.39 (m, 6H, thiophene, Ph-NH, OH); 3.51 (m, 2H,CH₂—NHCO); 2.89 (m, 2H, CH₂-Ph-NH); 1.38 (s, 18H, 2×tBu). IR: ν_(OH):3624 cm⁻¹; ν_(C═O) (amide): 1631 cm⁻¹; ν_(C═N) (amidine): 1577 cm⁻¹.

Example 29N-{4-(4-[2-(3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl)-1-oxo-ethyl]-1-piperazinyl)phenyl}-2-thiophene-carboximidamidehydrochloride: 29

The experimental protocol used is the same as that described for thecompound 9, with 3,5-di-tert-butyl-4-hydroxyphenylacetic acid replacingthe 3,5-di-tert-butyl-4-hydroxybenzoic acid in the first stage ofsynthesis. Yellow powder. Melting point: 176-180° C.

NMR ¹H (400 MHz, DMSO d6, δ): 11.30 (wide s, 1H, NH⁺); 9.70 (wide s, 1H,NH⁺); 8.65 (wide s, 1H, NH⁺); 8.10 (wide s, 2H, thiophene); 7.35 (wides, 1H, thiophene); 7.12 (m, 4H, Ph-N); 6.95 (s, 2H, Ph-OH); 6.80 (wides, 1H, OH); 3.60 (wide s, 6H, piperazine, CH₂CO); 3.10 (m, 4H,piperazine); 1.35 (s, 18H, 2× tBu). IR: ν_(OH): 3620 cm⁻¹; ν_(C═O)(ester): 1638 cm⁻¹: ν_(C═N) (amidine): 1612 cm⁻¹.

Example 30 2-{4-[(2-thienyl(imino)methyl)amino]phenyl}ethyl3,5-bis-(1,1-dimethylethyl)-4-hydroxy-benzoate hydrochloride: 30

30.1) 2-(4-nitrophenyl)ethyl3,5-bis-(1,1-dimethylethyl)-4-hydroxybenzoate:

In a 250 ml flask containing 80 ml of THF, under an argon atmosphere,2.45 g (9.8 mmoles) of 3,5-di-tert-butyl-4-hydroxybenzoic acid, 1.8 g(10.8 mmoles) of 4-nitrobenzene-ethanol and 2.2 g (10.8 mmoles) ofdicyclohexylcarbodiimide are introduced successively, under agitation.The reaction medium is agitated for 15 hours at 20° C. and theprecipitate which appears is filtered out. The filtrate is washed with2×30 ml of a saturated NaCl solution, the organic phase is dried overmagnesium sulphate, filtered and concentrated under vacuum. The residueis then crystallized using di-isopropyl ether. The solid is recovered byfiltration and 2.4 g (62%) of white crystals are obtained after drying.Melting point: 123.5-124.5° C.

NMR ¹H (100 MHz, CDCl₃, δ): 7.85 (m, 4H, Ph-NO₂); 7.80 (s, 2H, Ph-OH);5.70 (s, 1H, OH); 4.50 (m, 2H, O—CH₂); 3.20 (m, 2H, CH₂); 1.40 (s, 18H,2× tBu).

30.2) 2-(4-aminophenyl)ethyl3,5-bis-(1,1-dimethylethyl)-4-hydroxy-benzoate:

The experimental protocol is the same as that described for intermediate2.2, with intermediate 30.1 replacing the3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-[(4-nitrophenyl)-methyl]-benzamide.A white powder is obtained with a yield of 50%. Melting point: 135-136°C.

NMR ¹H (400 MHz, DMSO d6, δ): 7.75 (s, 2H, Ph-OH); 6.70 (m, 4H, Ph-N);4.90 (wide s, 1H, OH); 4.25 (m, 2H, O—CH₂); 3.30 (wide s, 2H, NH₂); 2.80(m, 2H, CH₂); 1.40 (s, 18H, 2×tBu).

30.3) 2-{4-[(2-thienyl(imino)methyl)amino]phenyl}ethyl3,5-bis-(1,1-dimethylethyl)-4-hydroxy-benzoate hydrochloride: 30

The experimental protocol is the same as that described for intermediate1.3, with intermediate 30.2 replacing the3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-(4-aminophenyl)-benzamide. Awhite solid is obtained with a yield of 26%. Melting point: 145-150° C.

NMR ¹H (400 MHz, DMSO d6, δ): 11.50 (wide s, 1H, NH⁺); 9.80 (wide s, 1H,NH⁺); 8.90 (wide s, 1H, NH⁺); 8.20 (wide s, 2H, thiophene); 7.85 (s, 1H,OH); 7.75 (s, 2H, Ph-OH); 7.47 (m, 5H, Ph-N, thiophene); 4.41 (m, 2H,O—CH₂); 3.08 (m, 2H, CH₂);1.40 (s, 18H, 2×tBu). IR: ν_(C═O) (ester):1700 cm⁻¹; ν_(C═N) (amidine): 1592 cm⁻¹.

Example 31 2-{3-[(2-thienyl(imino)methyl)amino]phenyl}ethyl3,5-bis-(1,1-dimethylethyl)-4-hydroxy-benzoate hydrochloride: 31

The experimental protocol used is the same as that described for thecompound 30, with 3-nitrobenzene-ethanol replacing the4-nitrobenzene-ethanol in the first stage of synthesis. Pale yellowpowder. Melting point: 145-148° C.

NMR ¹H (400 MHz, DMSO d6, δ): 11.50 (wide s, 1H, NH⁺); 9.82 (wide s, 1H,NH⁺); 8.99 (wide s, 1H, NH⁺); 8.15 (m, 2H, thiophene); 7.81 (s, 1H, OH);7.75 (s, 2H, Ph-OH); 7.41 (m, 5H, Ph-N, thiophene); 4.41 (m, 2H, O—CH₂);3.08 (m, 2H, CH₂); 1.38 (s, 18H, 2×tBu). IR: ν_(OH): 3620 cm⁻¹; ν_(C═O)(ester): 1707 cm⁻¹; ν_(C═N) (amidine): 1654 cm⁻¹.

Example 32 2-{2-[(2-thienyl(imino)methyl)amino]phenyl}ethyl3,5-bis-(1,1-dimethylethyl)-4-hydroxy-benzoate hydrochloride: 32

The experimental protocol used is the same as that described forcompound 30, with 2-nitrobenzene-ethanol replacing the4-nitrobenzene-ethanol in the first stage of synthesis. Beige powder.Melting point: 139-145° C.

NMR ¹H (400 MHz, DMSO d6, δ): 11.50 (wide s, 1H, NH⁺); 9.80 (wide s, 1H,NH⁺); 8.65 (wide s, 1H, NH⁺); 8.15 (m, 2H, thiophene); 7.80 (s, 1H, OH);7.70 (s, 2H, Ph-OH); 7.60 (m, 1H, Ph); 7.45 (m, 3H, Ph); 7.35 (s, 1H,thiophene); 4.40 (m, 2H, O—CH₂); 3.00 (m, 2H, CH₂); 1.35 (s, 18H,2×tBu). IR: ν_(C═O) (ester): 1728 cm⁻¹; ν_(C═N) (amidine): 1649 cm⁻¹.

Pharmacological Study of the Products of the Invention

Study of the Effects on Neuronal Constitutive NO Synthase of a Rat'sCerebellum

The inhibitory activity of the products of the invention is determinedby measuring their effects on the conversion by NO synthase of[³H]L-arginine into [³H]L-citrulline according to the modified method ofBredt and Snyder (Proc. Natl. Acad. Sci. USA, (1990) 87: 682-685). Thecerebellums of Sprague-Dawley rats (300 g—Charles River) are rapidlyremoved, dissected at 4° C. and homogenized in a volume of extractionbuffer (HEPES 50 mM, EDTA 1 mM, pH 7.4, pepstatin A 10 mg/ml, leupeptin10 mg/ml). The homogenates are then centrifuged at 21000 g for 15 min at4° C. Dosage is carried out in glass test tubes in which 100 μl ofincubation buffer containing 100 mM of HEPES (pH 7.4), 2 mM of EDTA, 2.5mM of CaCl₂, 2 mM of dithiotreitol, 2 mM of reduced NADPH and 10 μg/mlof calmodulin are distributed. 25 μl of a solution containing 100 nM of[³H]L-arginine (Specific activity: 56.4 Ci/mmole, Amersham) and 40 μM ofnon-radioactive L-arginine is added. The reaction is initiated by adding50 μl of homogenate, the final volume being 200 μl (the missing 25 μlare either water or the tested product). After 15 min, the reaction isstopped with 2 ml of stopping buffer (20 mM of HEPES, pH 5.5, 2 mM ofEDTA). After placing the samples on a 1 ml column of DOWEX resin, theradioactivity is quantified by a liquid scintillation spectrometer. Thecompounds of examples 6, 7, 13 and 14 described above show an IC₅₀ lowerthan 3.5 μM.

Study of the Effects on Lipidic Peroxidation of the Cerebral Cortex of aRat

The inhibitory activity of the products of the invention is determinedby measuring their effects on the degree of lipidic peroxidation,determined by the concentration of malondialdehyde (MDA). The MDAproduced by peroxidation of unsaturated fatty acids is a good indicationof lipidic peroxidation (H Esterbauer and K H Cheeseman, Meth. Enzymol.(1990) 186: 407-421). Male Sprague Dawley rats of 200 to 250 g (CharlesRiver) were sacrificed by decapitation. The cerebral cortex is removed,then homogenized using a Thomas potter in a 20 mM Tris-HCl buffer,pH=7.4. The homogenate was centrifuged twice at 50000 g for 10 minutesat 4° C. The pellet is maintained at −80° C. On the day of theexperiment, the pellet is replaced in suspension at a concentration of 1g/15 ml and centrifuged at 515 g for 10 minutes at 4° C. The supernatantis used immediately to determine the lipidic peroxidation. Thehomogenate of rat's cerebral cortex (500 μl) is incubated at 37° C. for15 minutes in the presence of the compounds to be tested or of solvent(10 μl). The lipidic peroxidation reaction is initiated by adding 50 μlof FeCl₂ at 1 mM, EDTA at 1 mM and ascorbic acid at 4 mM. After 30minutes of incubation at 37° C., the reaction is stopped by adding 50 μlof a solution of hydroxylated di tertio butyl toluene (BHT, 0.2%). TheMDA is quantified using a colorimetric test, by reacting a chromogenicreagent (R), N-methyl-2-phenylindol (650 μl) with 200 μl of thehomogenate for 1 hour at 45° C. The condensation of an MDA molecule withtwo molecules of reagent R produce a stable chromophore the maximumabsorbence wavelength of which is equal to 586 nm. (Caldwell et al.European J. Pharmacol. (1995) 285, 203-206). The compounds of Examples5, 8, 9, 10, 12, 13, 14, 16, 17, 18, 19, 20, 21, 26 and 27 describedabove all show an IC₅₀ lower than 30 μM.

What is claimed is:
 1. A compound selected from the group consisting ofa compound of the formula

wherein A is

R₁ and R₂ are individually selected from the group consisting ofhydrogen, halogen, —OH, alkyl of 1 to 6 carbon atoms and alkoxy of 1 to6 carbon atoms, R₃ is selected from the group consisting of hydrogen,alkyl of 1 to 6 carbon atoms and —COR₄, R₄ is alkyl of 1 to 6 carbonatoms, B is selected from the group consisting of thiophene, furan, andpyrrole, X is selected from the group consisting of —Z₁—, —Z₁CO—,—CH═CH═CO—, —Z₁NR₃—CO—, —Z—NR₃—CS—, —Z₁NR₃—SO₂— and a single bond, Y isselected from the group consisting of —Z₂—Q—, —NR₃—Z₂—Q—, —NR₃—CO—Z₂—Q,—NR₃—NH—CO—Z₂—, —NH—NH—Z₂—, —NR₃—O—Z₂—, —NR₃—SO₂—NR₃—Z₂—, —OZ₂—Q—,—O—CO—Z₂—Q— and —S—Z₃—Q—, Q is selected from the group consisting of asingle bond, —OZ₃—, —SZ₂— and —NR₃—Z₃, Z₁, Z₂ and Z₃ are individuallyselected from the group consisting of a single bond and alkylene of 1 to6 carbon atoms, R₆ is hydrogen or —OH and its non-toxic,pharmaceutically acceptable salts with the proviso that it is not thecompound of the formula


2. A compound of claim 1 wherein A is


3. A compound according to claim 1 selected from the group consistingof:3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-{4-[(2-thienyl(imino)methyl)amino]phenyl}-benzamide;3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-{4-[[(2-thienyl(imino)methyl)amino]-phenyl]methyl}-benzamide;4-acetoxy-3,5-dimethoxy-N-{4-[[(2-thienyl(imino)methyl)amino]phenyl]methyl}-benzamide;3,5-dimethoxy-4-hydroxy-N-{4-[[(2-thienyl(imino)methyl)amino]phenyl]methyl}-benzamide;3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-{4-[2-[(2-thienyl(imino)methyl)amino]phenyl]ethyl}-benzamide;4-acetoxy-3,5-dimethoxy-N-{4-[2-[(2-thienyl(imino)methyl)-amino]phenyl]ethyl}-benzamide;3,5-dimethoxy-4-hydroxy-N-{4-[2-[(2-thienyl(imino)methyl)-amino]phenyl]ethyl}-benzamide;3,4,5-trihydroxy-N-{4-[2-[(2-thienyl(imino)methyl)-amino]phenyl]ethyl}-benzamide;3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-N-{4-[(2-thienyl(imino)methyl)amino]phenyl}-2H-1-benzopyran-2-carboxamide;3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-{3-[[(2-thienyl(imino)methyl)amino]phenyl]methyl}-benzamide;N-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N′-{{4-[(2-thienyl(imino)methyl)amino]phenyl}methyl}-urea:N-[5-[{3-(3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl)-1-oxo-2-propenyl}amino]-2-hydroxyphenyl]-2-thiophenecarboximidamide;N-[3-[{3-(3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl)-1-oxo-2-propenyl}-amino]-4-hydroxyphenyl]-2-thiophenecarboximidamide;N-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N′-{{4-[(2-thienyl(imino)methyl)amino]phenyl}carbonylamino}-urea;N-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N′-{{4-[(2-thieny(imino)methyl)amino]phenyl}methyl}-thiourea;N-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N′-{2-{4-[(2-thienyl(imino)methyl)amino]phenyl}ethyl}-urea;3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-{2-[3-[(2-thienyl(imino)methyl)amino]phenyl]ethyl}-benzamide;2-{4-[(2-thienyl(imino)methyl)amino]phenyl}ethyl3,5-bis-(1,1-dimethylethyl)-4-hydroxy-benzoate;2-{3-[(2-thienyl(imino)methyl)amino]phenyl}ethyl3,5-bis-(1,1-dimethylethyl)-4-hydroxy-benzoate;2-{2-[(2-thienyl(imino)methyl)amino]phenyl}ethyl3,5-bis-(1,1-dimethylethyl)-4-hydroxy-benzoate; and the pharmaceuticallyacceptable salts thereof.
 4. A compound of claim 1 selected from thegroup consisting of3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-[4-[2-thienyl(imino)methyl-amino]phenyl]ethyl]benzamide;3,4,5-trihydroxy-N-[4-[2-[(2-thienyl(imino)methyl)amino]phenyl]ethyl]-benzamide;3,4-dihydro-6-hydroxy-2,5,7,8-tetrmethyl-N-[4-[(2-thienyl(imino)methyl)amino]phenyl]-2H-1-benzopyran-2-carboxamide;3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-[3-[[(2-thienyl-(imino)methyl)amino]phenyl]methyl]-benzamide;N-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N′-[-4-[(2-thienyl(imino)methyl)amino]phenyl]methyl]-urea;N-[5-[3-(3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl)-1-oxo-2-propenyl]-amino[2-hydroxyphenyl]-2-thiophenecarboximidamide;N-[3-[[3-(3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl)-1-oxo-2-propenyl]-amino]-4-hydroxyphenyl]-2-thiophenecarboximidamine;andN-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N′-[[4-[(2-thienyl(imino)methyl)amino]phenyl]carbonylamino-urea.5. A process for the preparation of a compound of claim 1 comprisingreacting a compound of the formula

wherein A, X, Y and R₆ are defined as in claim 1 with a compound of theformula

wherein B is defined as in claim 1 and L is a leaving group in a loweralkanol to obtain a compound of claim
 1. 6. A neuronal NO synthaseinhibitory composition comprising a neuronal NO synthase inhibitorilyeffective amount of claim 1 and an insert pharmaceutical carrier.
 7. Ainductible NO synthase inhibitory composition comprising a neuronal NOsynthase inhibitorily effective amount of claim 1 and an insertpharmaceutical carrier.
 8. A method of inhibiting neuronal NO synthaseactivity in warm-blooded animals comprising administering towarm-blooded animals an neuronal NO synthase inhibitorily effectiveamount of a compound of claim
 1. 9. A method of inhibiting inductible NOsynthase activity in warm-blooded animals comprising administering towarm-blooded animals an neuronal NO synthase inhibitorily effectiveamount of a compound of claim
 1. 10. A method of inhibiting lipidicperoxidation in warm-blooded animals comprising administering towarm-blooded animals a lipidic peroxidation inhibitorily effectiveamount of claim
 1. 11. A compound of claim 1 wherein A is

wherein X is —CO— or —NHCO— and Y is selected from the group consistingof —NH—Z₂Q and piperazine, Q is selected from the group consisting of asingle bond, —OZ₃, NR₃—Z₃ and —SZ₃, Z₂, and Z₃ are individually a singlebond or alkylene of 1 to 6 carbon atoms and R₃ is hydrogen or alkyl of 1to 6 carbon atoms.
 12. A compound of claim 1 selected from the groupconsisting of4-acetoxy-3,5-dimethoxy-N-[4-[2-[2-thienyl-(iminomethyl)-amino]phenyl]ethyl]benzamide;and3,5-dimethoxy-4-hydroxy-N-[4-[2-[2-thienyl-iminomethyl)-amino]phenyl]ethyl]-benzamide.